Rho GTP酶在白血病细胞行为异常及与骨髓微环境相互作用异常中的意义
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摘要
造血微环境是维持造血干细胞自我更新潜能、制约细胞过度增殖、确保子细胞有序分化的重要场所,骨髓微环境中造血干细胞与基质细胞的粘附及细胞迁移的有序状态决定了造血干细胞的正常发育,有序状态的破坏使造血干细胞逃离微环境的制约,可能导致造血干细胞自我更新失衡及白血病细胞恶性行为的获得。
Rho GTP酶是Ras超家族中小分子量G蛋白的成员之一,是一类分子量为20-30kD的GTP结合蛋白。Rho GTP酶家族是连接细胞外信号与肌动蛋白细胞骨架系统的关键因子,是调控细胞极性化和细胞骨架重塑的关键蛋白,调控着肌动蛋白细胞骨架的动力学。细胞黏附丧失及启动迁移的细胞内在分子机制是Rho GTP酶的上调和活化。为确定骨髓微环境与造血细胞相互作用异常在白血病中的作用,我们以Rho GTP酶家族成员为研究对象,通过确定Rho GTP酶家族成员RhoA、Rac1及CDC42在白血病细胞的表达异常,及Racl的高表达及活化在白血病细胞行为异常及在白血病细胞与骨髓微环境相互作用异常中的意义,以阐明其在白血病发生中的作用,具体研究内容如下：
1.白血病患者RhoA、Rac1和CDC42的蛋白表达：应用Western-blot方法检测88例急性白血病患者和22例正常骨髓移植供者骨髓单个核细胞的Rac1相对表达水平,同时检测54例急性白血病RhoA和CDC42的相对表达水平,发现与正常人相比,白血病患者RhoA. Rac1和CDC42表达升高,非配对t检验进行统计学分析,均具有统计学差异(P<0.01)。
2.Racl的高表达在白血病细胞行为中的作用：通过小RNA方法干扰白血病细胞系KG1-a和HL-60细胞内Racl的表达,测定干扰后细胞的迁移及增殖能力,结果发现,细胞的迁移、增殖及集落形成能力均降低。
3. Rac1-GTP酶的活化在白血病细胞中的作用：采用Rac的特异性抑制剂处理白血病细胞,测定细胞的迁移及增殖能力,结果显示,细胞的迁移和增殖能力均显著降低,从而证实白血病细胞中Racl-GTP酶的活化与白血病细胞迁移活跃及增殖旺盛有关。进一步我们构建表达组成性活化型Rac1的慢病毒载体和表达负显性抑制型Rac1的慢病毒载体,将慢病毒感染KG1-a细胞。GST-pull down实验确定了病毒感染的细胞内Rac1-GTP酶的水平活化后,对感染细胞的生物学功能进行了检测,结果发现感染组成性活化型Rac1慢病毒载体的KG1-a细胞的迁移能力增强,对VP16的耐药性增加,在骨髓基质细胞上粘附能力明显降低、迁移活跃；感染负显性抑制型Rac1慢病毒载体的KG1-a细胞行为则相反,表明Rac1-GTP的异常活化与白血病细胞迁移活跃、粘附降低及对化疗药物VP16的耐药性有关。
以上研究提示白血病细胞由于Racl的高表达及异常活化导致迁移及增殖能力增加,细胞粘附能力降低,提示白血病细胞与骨髓基质细胞相互作用异常可能导致白血病细胞逃离骨髓微环境的制约,影响造血干细胞的正常发育,这些改变可能与白血病的发生发展有关。
Hematopoietic stem cells (HSCs) reside in a complex bone marrow (BM) microenvironment, which is critical for regulating HSCs behavior and fate, including self-renewal, proliferation and differentiation. HSCs homeostasis in each of stem-cell niches is achieved by the delicate balance of cell adhesion and cell motility among distinct location regions and is important for the development of hematopoietic stem cells. Disruption of this homeostasis leads to many detrimental pathological conditions that implicated in HSCs' unbalanced self-renewal and abnormal behaviors.
Rho GTPase is a 20-30KD GTP-binding protein that belongs to the Ras superfamily of small G proteins. Rho GTPase family is a key factor that connects extracellular signal and actin cytoskeleton system and regulates cell polarity, cytoskeletal rearrange and actin cytoskeletal dynamic. It has become evident that overexpression and activation of Rho GTPases family are important machanism regulating cell adhesion and migration. To determine the role of abnormal interaction of hematopoitic cells with bone marrow microenvironment in leukemogenesis, we investigated the expression and significance of Rho GTPase family members in leukemic cells. Through detecting the proteins levels of Rac1,RhoA and CDC42 in leukemia patients and determining the role of overexpression and activition of Rac1 in the abnormal behavior of leukemia cells and aberrant interaction of leukemic cells with bone marrow microenvironment, we elucidate that abnormal Rho GTPase associated microenvironment may lead to malignant hematopoiesis.
The details are as follows:
1. The expression of RhoA. Rac1 and CDC42 proteins in leukemia patients:via Western-blot assay, we detected the relative expression of Rac1 in BMMC samples that were separated from 88 primary acute leukemia patients and 22 normal donors. Meanwhile the relative expressions of RhoA and CDC42 in 54 primary acute leukemia patients were also detected. The results showed that expression levels of RhoA、Rac1 and CDC42 protein in leukemia patients were significantly higher than that of normal samples with P＜0.01.
2. The role of high expression of Rac1 in leukemia cells:Through interfering the expression of Rac1 in leukemia cell lines KG1-a and HL-60, we then determined the migration and proliferation ability of leukemic cells. The results showed that siRNA mediated silencing of Rac1 in leukemia cell lines induced inhibition of cell migration, proliferation and colony formation.
3. The role of activition of Rac1-GTPase in leukemia cells:Leukemia cells were further treated by Rac GTPase-specific small molecular inhibitor NSC23766. Cell migration and proliferation were then determined. The results showed that blocking Rac1 activity by NSC23766 suppressed cell migration and growth. We further constructed the lentivirus vector carrying cDNA of constitutively active Rac1 or dominant negative Rac1, and infected KG1-a cells. GST-pull down assays confirmed the activity of Rac1-GTPase in infected cells. Then we detected the biological function of infected cells. The results showed that KG1-a cells infected with constitutively active Rac1 lentiviral vector displayed significantly increased cell migration and resistant to VP16. Adhesion of constitutively active Rac1 lentiviral vector infected KG1-a cell with bone marrow matrix cells was significantly descreased. By contrast, the behavior of KG1-a cells that infected by dominant negative Rac1 vector is reverse. Our experiment results indicated that the abnormal activition of Rac1-GTP correlates with accelerated migration、descreased adhesion and resistant to chemotherapeutics VP16 of leukemia cells.
The above investigation suggests that overexpression and abnormal activition of Rac1 leads to efficient migration, vigorous proliferation and descreased adhesion. In bone marrow microenvironment, alterations of HSCs' migratory behavior might lead hematopoietic stem cells to escape from the restriction of microenvironment and obtains uncontrolled proliferation ability. Those alterations may contribute to the leukemia development and progression.
Rho GTP酶是Ras超家族中小分子量G蛋白的成员之一,是一类分子量为20-30kD的GTP结合蛋白。Rho GTP酶家族是连接细胞外信号与肌动蛋白细胞骨架系统的关键因子,是调控细胞极性化和细胞骨架重塑的关键蛋白,调控着肌动蛋白细胞骨架的动力学。细胞黏附丧失及启动迁移的细胞内在分子机制是Rho GTP酶的上调和活化。为确定骨髓微环境与造血细胞相互作用异常在白血病中的作用,我们以Rho GTP酶家族成员为研究对象,通过确定Rho GTP酶家族成员RhoA、Rac1及CDC42在白血病细胞的表达异常,及Racl的高表达及活化在白血病细胞行为异常及在白血病细胞与骨髓微环境相互作用异常中的意义,以阐明其在白血病发生中的作用,具体研究内容如下：
1.白血病患者RhoA、Rac1和CDC42的蛋白表达：应用Western-blot方法检测88例急性白血病患者和22例正常骨髓移植供者骨髓单个核细胞的Rac1相对表达水平,同时检测54例急性白血病RhoA和CDC42的相对表达水平,发现与正常人相比,白血病患者RhoA. Rac1和CDC42表达升高,非配对t检验进行统计学分析,均具有统计学差异(P<0.01)。
2.Racl的高表达在白血病细胞行为中的作用：通过小RNA方法干扰白血病细胞系KG1-a和HL-60细胞内Racl的表达,测定干扰后细胞的迁移及增殖能力,结果发现,细胞的迁移、增殖及集落形成能力均降低。
3. Rac1-GTP酶的活化在白血病细胞中的作用：采用Rac的特异性抑制剂处理白血病细胞,测定细胞的迁移及增殖能力,结果显示,细胞的迁移和增殖能力均显著降低,从而证实白血病细胞中Racl-GTP酶的活化与白血病细胞迁移活跃及增殖旺盛有关。进一步我们构建表达组成性活化型Rac1的慢病毒载体和表达负显性抑制型Rac1的慢病毒载体,将慢病毒感染KG1-a细胞。GST-pull down实验确定了病毒感染的细胞内Rac1-GTP酶的水平活化后,对感染细胞的生物学功能进行了检测,结果发现感染组成性活化型Rac1慢病毒载体的KG1-a细胞的迁移能力增强,对VP16的耐药性增加,在骨髓基质细胞上粘附能力明显降低、迁移活跃；感染负显性抑制型Rac1慢病毒载体的KG1-a细胞行为则相反,表明Rac1-GTP的异常活化与白血病细胞迁移活跃、粘附降低及对化疗药物VP16的耐药性有关。
以上研究提示白血病细胞由于Racl的高表达及异常活化导致迁移及增殖能力增加,细胞粘附能力降低,提示白血病细胞与骨髓基质细胞相互作用异常可能导致白血病细胞逃离骨髓微环境的制约,影响造血干细胞的正常发育,这些改变可能与白血病的发生发展有关。
Hematopoietic stem cells (HSCs) reside in a complex bone marrow (BM) microenvironment, which is critical for regulating HSCs behavior and fate, including self-renewal, proliferation and differentiation. HSCs homeostasis in each of stem-cell niches is achieved by the delicate balance of cell adhesion and cell motility among distinct location regions and is important for the development of hematopoietic stem cells. Disruption of this homeostasis leads to many detrimental pathological conditions that implicated in HSCs' unbalanced self-renewal and abnormal behaviors.
Rho GTPase is a 20-30KD GTP-binding protein that belongs to the Ras superfamily of small G proteins. Rho GTPase family is a key factor that connects extracellular signal and actin cytoskeleton system and regulates cell polarity, cytoskeletal rearrange and actin cytoskeletal dynamic. It has become evident that overexpression and activation of Rho GTPases family are important machanism regulating cell adhesion and migration. To determine the role of abnormal interaction of hematopoitic cells with bone marrow microenvironment in leukemogenesis, we investigated the expression and significance of Rho GTPase family members in leukemic cells. Through detecting the proteins levels of Rac1,RhoA and CDC42 in leukemia patients and determining the role of overexpression and activition of Rac1 in the abnormal behavior of leukemia cells and aberrant interaction of leukemic cells with bone marrow microenvironment, we elucidate that abnormal Rho GTPase associated microenvironment may lead to malignant hematopoiesis.
The details are as follows:
1. The expression of RhoA. Rac1 and CDC42 proteins in leukemia patients:via Western-blot assay, we detected the relative expression of Rac1 in BMMC samples that were separated from 88 primary acute leukemia patients and 22 normal donors. Meanwhile the relative expressions of RhoA and CDC42 in 54 primary acute leukemia patients were also detected. The results showed that expression levels of RhoA、Rac1 and CDC42 protein in leukemia patients were significantly higher than that of normal samples with P＜0.01.
2. The role of high expression of Rac1 in leukemia cells:Through interfering the expression of Rac1 in leukemia cell lines KG1-a and HL-60, we then determined the migration and proliferation ability of leukemic cells. The results showed that siRNA mediated silencing of Rac1 in leukemia cell lines induced inhibition of cell migration, proliferation and colony formation.
3. The role of activition of Rac1-GTPase in leukemia cells:Leukemia cells were further treated by Rac GTPase-specific small molecular inhibitor NSC23766. Cell migration and proliferation were then determined. The results showed that blocking Rac1 activity by NSC23766 suppressed cell migration and growth. We further constructed the lentivirus vector carrying cDNA of constitutively active Rac1 or dominant negative Rac1, and infected KG1-a cells. GST-pull down assays confirmed the activity of Rac1-GTPase in infected cells. Then we detected the biological function of infected cells. The results showed that KG1-a cells infected with constitutively active Rac1 lentiviral vector displayed significantly increased cell migration and resistant to VP16. Adhesion of constitutively active Rac1 lentiviral vector infected KG1-a cell with bone marrow matrix cells was significantly descreased. By contrast, the behavior of KG1-a cells that infected by dominant negative Rac1 vector is reverse. Our experiment results indicated that the abnormal activition of Rac1-GTP correlates with accelerated migration、descreased adhesion and resistant to chemotherapeutics VP16 of leukemia cells.
The above investigation suggests that overexpression and abnormal activition of Rac1 leads to efficient migration, vigorous proliferation and descreased adhesion. In bone marrow microenvironment, alterations of HSCs' migratory behavior might lead hematopoietic stem cells to escape from the restriction of microenvironment and obtains uncontrolled proliferation ability. Those alterations may contribute to the leukemia development and progression.
引文
1. Tavassoli M (1975) Studies on hemopoietic microenvironments. Report of a workshop held in La Jolla,, California, August 8-9,1974. Exp Hematol 3:213-226.
2. Wolf NS (1979) The haemopoietic microenvironment. Clin Haematol 8:469-500.
3. Dexter TM (1982) Stromal cell associated haemopoiesis. J Cell Physiol Suppl 1:87-94.
4. Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4:7-25.
5. Zhu J, Emerson SG (2004) A new bone to pick:osteoblasts and the haematopoietic stem-cell niche. Bioessays 26:595-599.
6. Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 29:356-370.
7. Caussinus E, Gonzalez C (2005) Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet 37:1125-1129.
8. Rossman KL, Der CJ, Sondek J (2005) GEF means go:turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6:167-180.
9. Peck J, Douglas Gt, Wu CH, Burbelo PD (2002) Human RhoGAP domain-containing proteins:structure, function and evolutionary relationships. FEBS Lett 528:27-34.
10. Winter-Vann AM, Casey PJ (2005) Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer 5:405-412.
11. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629-635.
12. Theriault BL, Shepherd TG, Mujoomdar ML, Nachtigal MW (2007) BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells. Carcinogenesis 28: 1153-1162.
13. Patel V, Rosenfeldt HM, Lyons R, Servitja JM, Bustelo XR, et al. (2007) Persistent activation of Rac1 in squamous carcinomas of the head and neck:evidence for an EGFR/Vav2 signaling axis involved in cell invasion. Carcinogenesis 28:1145-1152.
14. Pan ZZ, Bruening W, Godwin AK (2006) Involvement of RHO GTPases and ERK in synuclein-gamma enhanced cancer cell motility. Int J Oncol 29:1201-1205.
15. Merajver SD, Usmani SZ (2005) Multifaceted role of Rho proteins in angiogenesis. J Mammary Gland Biol Neoplasia 10:291-298.
16. Fukui K, Tamura S, Wada A, Kamada Y, Sawai Y, et al. (2006) Expression and prognostic role of RhoA GTPases in hepatocellular carcinoma. J Cancer Res Clin Oncol 132: 627-633.
17. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509-514.
18. Jaffe AB, Hall A (2005) Rho GTPases:biochemistry and biology. Annu Rev Cell Dev Biol 21:247-269.
19. Wang J, Rao Q, Wang M, Wei H, Xing H, et al. (2009) Overexpression of Rac1 in leukemia patients and its role in leukemia cell migration and growth. Biochem Biophys Res Commun 386:769-774.
20. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005) Opinion:migrating cancer stem cells-an integrated concept of malignant tumour progression. Nat Rev Cancer 5: 744-749.
21. Cherry LK, Li X, Schwab P, Lim B, Klickstein LB (2004) RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes. Nat Immunol 5:961-967.
22. Sanchez-Aguilera A, Rattmann I, Drew DZ, Muller LU, Summey V, et al. (2010) Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia. Leukemia 24:97-104.
23. Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, et al. (2000) Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor:evidence for its fusion with MLL in acute myeloid leukemia. Proc Natl Acad Sci U S A 97:2145-2150.
24. Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, et al. (2001) Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. J Biol Chem 276: 27145-27151.
25. Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, et al. (2000) The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q. Proc Natl Acad Sci U S A 97:9168-9173.
26. Bojesen SE, Ammerpohl O, Weinhausl A, Haas OA, Mettal H, et al. (2006) Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome. Br J Cancer 94:323-332.
27. Cleverley SC, Costello PS, Henning SW, Cantrell DA (2000) Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma. Oncogene 19:13-20.
28. Wei J, Wunderlich M, Fox C, Alvarez S, Cigudosa JC, et al. (2008) Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13: 483-495.
29. Yang FC, Atkinson SJ, Gu Y, Borneo JB, Roberts AW, et al. (2001) Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization. Proc Natl Acad Sci U S A 98:5614-5618.
1. Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family:regulation, effectors and functions in vivo. Bioessays 29: 356-370.
2. Rossman KL, Der CJ, Sondek J (2005) GEF means go:turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6: 167-180.
3. Peck J, Douglas Gt, Wu CH, Burbelo PD (2002) Human RhoGAP domain-containing proteins:structure, function and evolutionary relationships. FEBS Lett 528:27-34.
4. Winter-Vann AM, Casey PJ (2005) Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer 5:405-412.
5. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, et al. (1999) Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285:895-898.
6. Pollard TD, Blanchoin L, Mullins RD (2000) Molecular mechanisms controlling actin filament dynamics in nonmuscle cells. Annu Rev Biophys Biomol Struct 29:545-576.
7. Ishizaki T, Morishima Y, Okamoto M, Furuyashiki T, Kato T, et al. (2001) Coordination of microtubules and the actin cytoskeleton by the Rho effector mDia1. Nat Cell Biol 3:8-14.
8. Stephens L, Ellson C, Hawkins P (2002) Roles of PI3Ks in leukocyte chemotaxis and phagocytosis. Curr Opin Cell Biol 14:203-213.
9. Etienne-Manneville S, Hall A (2001) Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta. Cell 106: 489-498.
10. Tanegashima K, Zhao H, Dawid IB (2008) WGEF activates Rho in the Wnt-PCP pathway and controls convergent extension in Xenopus gastrulation. EMBO J 27:606-617.
11. Kovar DR (2006) Molecular details of formin-mediated actin assembly. Curr Opin Cell Biol 18:11-17.
12. Liu W, Sato A, Khadka D, Bharti R, Diaz H, et al. (2008) Mechanism of activation of the Formin protein Daam1. Proc Natl Acad Sci U S A 105: 210-215.
13. Lu J, Meng W, Poy F, Maiti S, Goode BL, et al. (2007) Structure of the FH2 domain of Daam1:implications for formin regulation of actin assembly. J Mol Biol 369:1258-1269.
14. Aspenstrom P, Richnau N, Johansson AS (2006) The diaphanous-related formin DAAM1 collaborates with the Rho GTPases RhoA and Cdc42, CIP4 and Src in regulating cell morphogenesis and actin dynamics. Exp Cell Res 312:2180-2194.
15. Jaffe AB, Hall A (2005) Rho GTPases:biochemistry and biology. Annu Rev Cell Dev Biol 21:247-269.
16. Takaishi K, Sasaki T, Kotani H, Nishioka H, Takai Y (1997) Regulation of cell-cell adhesion by rac and rho small G proteins in MDCK cells. J Cell Biol 139:1047-1059.
17. Braga VM, Machesky LM, Hall A, Hotchin NA (1997) The small GTPases Rho and Rac are required for the establishment of cadherin-dependent cell-cell contacts. J Cell Biol 137:1421-1431.
18. Boureux A, Vignal E, Faure S, Fort P (2007) Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol 24:203-216.
19. Katoh H, Negishi M (2003) RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature 424:461-464.
20. Ridley AJ (2001) Rho GTPases and cell migration. J Cell Sci 114: 2713-2722.
21. Wells CM, Walmsley M, Ooi S, Tybulewicz V, Ridley AJ (2004) Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration. J Cell Sci 117:1259-1268.
22. Sun CX, Downey GP, Zhu F, Koh AL, Thang H, et al. (2004) Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 104:3758-3765.
23. Roberts AW, Kim C, Zhen L, Lowe JB, Kapur R, et al. (1999) Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity 10: 183-196.
24. Takenawa T, Suetsugu S (2007) The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 8: 37-48.
25. Wang W, Eddy R, Condeelis J (2007) The cofilin pathway in breast cancer invasion and metastasis. Nat Rev Cancer 7:429-440.
26. Sun CX, Magalhaes MA, Glogauer M (2007) Rac1 and Rac2 differentially regulate actin free barbed end formation downstream of the fMLP receptor. J Cell Biol 179:239-245.
27. Yamauchi A, Kim C, Li S, Marchal CC, Towe J, et al. (2004) Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles. J Immunol 173:5971-5979.
28. Gupton SL, Gertler FB (2007) Filopodia:the fingers that do the walking. Sci STKE 2007:re5.
29. Chen F, Ma L, Parrini MC, Mao X, Lopez M, et al. (2000) Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability. Curr Biol 10:758-765.
30. Garvalov BK, Flynn KC, Neukirchen D, Meyn L, Teusch N, et al. (2007) Cdc42 regulates cofilin during the establishment of neuronal polarity. J Neurosci27:13117-13129.
31. Yang L, Wang L, Zheng Y (2006) Gene targeting of Cdc42 and Cdc42GAP affirms the critical involvement of Cdc42 in filopodia induction, directed migration, and proliferation in primary mouse embryonic fibroblasts. Mol Biol Cell 17:4675-4685.
32. Czuchra A, Wu X, Meyer H, van Hengel J, Schroeder T, et al. (2005) Cdc42 is not essential for filopodium formation, directed migration, cell polarization, and mitosis in fibroblastoid cells. Mol Biol Cell 16:4473-4484.
33. Garcia-Bernal D, Wright N, Sotillo-Mallo E, Nombela-Arrieta C, Stein JV, et al. (2005) Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin alpha4beta1. Mol Biol Cell 16:3223-3235.
34. Pradip D, Peng X, Durden DL (2003) Rac2 specificity in macrophage integrin signaling:potential role for Syk kinase. J Biol Chem 278:41661-41669.
35. Yang FC, Atkinson SJ, Gu Y, Borneo JB, Roberts AW, et al. (2001) Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization. Proc Natl Acad Sci U S A 98:5614-5618.
36. Jansen M, Yang FC, Cancelas JA, Bailey JR, Williams DA (2005) Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure. Stem Cells 23:335-346.
37. Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, et al. (2003) Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302:445-449.
38. Cancelas JA, Lee AW, Prabhakar R, Stringer KF, Zheng Y, et al. (2005) Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization. Nat Med 11:886-891.
39. Motegi F, Sugimoto A (2006) Sequential functioning of the ECT-2 RhoGEF, RHO-1 and CDC-42 establishes cell polarity in Caenorhabditis elegans embryos. Nat Cell Biol 8:978-985.
40. Rojas R, Ruiz WG, Leung SM, Jou TS, Apodaca G (2001) Cdc42-dependent modulation of tight junctions and membrane protein traffic in polarized Madin-Darby canine kidney cells. Mol Biol Cell 12:2257-2274.
41. Yang L, Wang L, Geiger H, Cancelas JA, Mo J, et al. (2007) Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow. Proc Natl Acad Sci U S A 104:5091-5096.
42. Cappello S, Attardo A, Wu X, Iwasato T, Itohara S, et al. (2006) The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface. Nat Neurosci 9:1099-1107.
43. Chen L, Liao G, Yang L, Campbell K, Nakafuku M, et al. (2006) Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly. Proc Natl Acad Sci U S A 103:16520-16525.
44. Watabe-Uchida M, Govek EE, Van Aelst L (2006) Regulators of Rho GTPases in neuronal development. J Neurosci 26:10633-10635.
45. Benitah SA, Frye M, Glogauer M, Watt FM (2005) Stem cell depletion through epidermal deletion of Rac1. Science 309:933-935.
46. Stramer B, Wood W, Galko MJ, Redd MJ, Jacinto A, et al. (2005) Live imaging of wound inflammation in Drosophila embryos reveals key roles for small GTPases during in vivo cell migration. J Cell Biol 168:567-573.
47. Srinivasan S, Wang F, Glavas S, Ott A, Hofmann F, et al. (2003) Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis. J Cell Biol 160:375-385.
48. Szczur K, Xu H, Atkinson S, Zheng Y, Filippi MD (2006) Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Blood 108:4205-4213.
49. Wu X, Quondamatteo F, Lefever T, Czuchra A, Meyer H, et al. (2006) Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin. Genes Dev 20:571-585.
50. Yang L, Wang L, Kalfa TA, Cancelas JA, Shang X, et al. (2007) Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis. Blood 110:3853-3861.
51. Chimini G, Chavrier P (2000) Function of Rho family proteins in actin dynamics during phagocytosis and engulfment. Nat Cell Biol 2:E191-196.
52. Koh AL, Sun CX, Zhu F, Glogauer M (2005) The role of Rac1 and Rac2 in bacterial killing. Cell Immunol 235:92-97.
53. Williams DA, Tao W, Yang F, Kim C, Gu Y, et al. (2000) Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood 96:1646-1654.
54. Hoppe AD, Swanson JA (2004) Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol Biol Cell 15:3509-3519.
55. Hall AB, Gakidis MA, Glogauer M, Wilsbacher JL, Gao S, et al. (2006) Requirements for Vav guanine nucleotide exchange factors and Rho GTPases in FcgammaR-and complement-mediated phagocytosis. Immunity 24:305-316.
56. Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19:1-49.
57. Chen TJ, Gehler S, Shaw AE, Bamburg JR, Letourneau PC (2006) Cdc42 participates in the regulation of ADF/cofilin and retinal growth cone filopodia by brain derived neurotrophic factor. J Neurobiol 66:103-114.
58. Koh CG (2006) Rho GTPases and their regulators in neuronal functions and development. Neurosignals 15:228-237.
59. Threadgill R, Bobb K, Ghosh A (1997) Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron 19:625-634.
60. Albertinazzi C, Gilardelli D, Paris S, Longhi R, de Curtis (?).(1998) Overexpression of a neural-specific rho family GTPase, cRac1B, selectively induces enhanced neuritogenesis and neurite branching in primary neurons. J Cell Biol 142:815-825.
61. Corbetta S, Gualdoni S, Albertinazzi C, Paris S, Croci L, et al. (2005) Generation and characterization of Rac3 knockout mice. Mol Cell Biol 25: 5763-5776.
62. Gualdoni S, Albertinazzi C, Corbetta S, Valtorta F, de Curtis I (2007) Normal levels of Rac1 are important for dendritic but not axonal development in hippocampal neurons. Biol Cell 99:455-464.
63. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629-635.
64. Lane J, Martin TA, Mansel RE, Jiang WG (2008) The expression and prognostic value of the guanine nucleotide exchange factors (GEFs) Trio, Vav1 and TIAM-1 in human breast cancer. Int Semin Surg Oncol 5:23.
65. Fukui K, Tamura S, Wada A, Kamada Y, Sawai Y, et al. (2006) Expression and prognostic role of RhoA GTPases in hepatocellular carcinoma. J Cancer Res Clin Oncol 132:627-633.
66. Li XR, Ji F, Ouyang J, Wu W, Qian LY, et al. (2006) Overexpression of RhoA is associated with poor prognosis in hepatocellular carcinoma. Eur J Surg Oncol 32:1130-1134.
67. Abraham MT, Kuriakose MA, Sacks PG, Yee H, Chiriboga L, et al. (2001) Motility-related proteins as markers for head and neck squamous cell cancer. Laryngoscope 111:1285-1289.
68. Adnane J, Seijo E, Chen Z, Bizouarn F, Leal M, et al. (2002) RhoB, not RhoA, represses the transcription of the transforming growth factor beta type II receptor by a mechanism involving activator protein 1. J Biol Chem 277: 8500-8507.
69. Fritz G, Just I, Kaina B (1999) Rho GTPases are over-expressed in human tumors. Int J Cancer 81:682-687.
70. Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, et al. (2003) Up-regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. Lab Invest 83:861-870.
71. Kamai T, Tsujii T, Arai K, Takagi K, Asami H, et al. (2003) Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res 9:2632-2641.
72. Pan Y, Bi F, Liu N, Xue Y, Yao X, et al. (2004) Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun 315:686-691.
73. Faried A, Faried LS, Usman N, Kato H, Kuwano H (2007) Clinical and prognostic significance of RhoA and RhoC gene expression in esophageal squamous cell carcinoma. Ann Surg Oncol 14:3593-3601.
74. Kamai T, Yamanishi T, Shirataki H, Takagi K, Asami H, et al. (2004) Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Clin Cancer Res 10:4799-4805.
75. Wheeler AP, Ridley AJ (2004) Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility. Exp Cell Res 301:43-49.
76. Henning SW, Galandrini R, Hall A, Cantrell DA (1997) The GTPase Rho has a critical regulatory role in thymus development. EMBO J 16:2397-2407.
77. Cleverley SC, Costello PS, Henning SW, Cantrell DA (2000) Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma. Oncogene 19:13-20.
78. Horiuchi A, Kikuchi N, Osada R, Wang C, Hayashi A, et al. (2008) Overexpression of RhoA enhances peritoneal dissemination:RhoA suppression with Lovastatin may be useful for ovarian cancer. Cancer Sci 99: 2532-2539.
79. Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, et al. (2000) Rac1 in human breast cancer:overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19:3013-3020.
80. Liu SY, Yen CY, Yang SC, Chiang WF, Chang KW (2004) Overexpression of Rac-1 small GTPase binding protein in oral squamous cell carcinoma. J Oral Maxillofac Surg 62:702-707.
81. Espina C, Cespedes MV, Garcia-Cabezas MA, Gomez del Pulgar MT, Boluda A, et al. (2008) A critical role for Rac1 in tumor progression of human colorectal adenocarcinoma cells. Am J Pathol 172:156-166.
82. Kissil JL, Walmsley MJ, Hanlon L, Haigis KM, Bender Kim CF, et al. (2007) Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res 67:8089-8094.
83. Harnois T, Constantin B, Rioux A, Grenioux E, Kitzis A, et al. (2003) Differential interaction and activation of Rho family GTPases by p210bcr-abl and p190bcr-abl. Oncogene 22:6445-6454.
84. Thomas EK, Cancelas JA, Chae HD, Cox AD, Keller PJ, et al. (2007) Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease. Cancer Cell 12: 467-478.
85. van Hengel J, D'Hooge P, Hooghe B, Wu X, Libbrecht L, et al. (2008) Continuous cell injury promotes hepatic tumorigenesis in cdc42-deficient mouse liver. Gastroenterology 134:781-792.
86. Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4:7-25.
87. Kiel MJ, Morrison SJ (2008) Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 8:290-301.
88. Tan BL, Yazicioglu MN, Ingram D, McCarthy J, Borneo J, et al. (2003) Genetic evidence for convergence of c-Kit-and alpha4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells. Blood 101:4725-4732.
89. del Pozo MA, Vicente-Manzanares M, Tejedor R, Serrador JM, Sanchez-Madrid F (1999) Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur J Immunol 29:3609-3620.
90. Ghiaur G, Ferkowicz MJ, Milsom MD, Bailey J, Witte D, et al. (2008) Rac1 is essential for intraembryonic hematopoiesis and for the initial seeding of fetal liver with definitive hematopoietic progenitor cells. Blood 111:3313-3321.
91. Wang L, Yang L, Filippi MD, Williams DA, Zheng Y (2006) Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment. Blood 107:98-105.
92. Xing Z, Ryan MA, Daria D, Nattamai KJ, Van Zant G, et al. (2006) Increased hematopoietic stem cell mobilization in aged mice. Blood 108:2190-2197.
93. Williams DA, Cancelas JA (2006) Leukaemia:niche retreats for stem cells. Nature 444:827-828.
94. Kondo M, Weissman IL, Akashi K (1997) Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91:661-672.
95. Akashi K, Traver D, Miyamoto T, Weissman IL (2000) A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404: 193-197.
96. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y (2004) Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A 101:7618-7623.
97. Ji P, Jayapal SR, Lodish HF (2008) Enucleation of cultured mouse fetal erythroblasts requires Rac GTPases and mDia2. Nat Cell Biol 10:314-321.
98. Kalfa TA, Pushkaran S, Mohandas N, Hartwig JH, Fowler VM, et al. (2006) Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood 108:3637-3645.
99. Borroto A, Gil D, Delgado P, Vicente-Manzanares M, Alcover A, et al. (2000) Rho regulates T cell receptor ITAM-induced lymphocyte spreading in an integrin-independent manner. Eur J Immunol 30:3403-3410.
100. Campbell KS (1999) Signal transduction from the B cell antigen-receptor. Curr Opin Immunol 11:256-264.
101. Gomez M, Tybulewicz V, Cantrell DA (2000) Control of pre-T cell proliferation and differentiation by the GTPase Rac-I. Nat Immunol 1: 348-352.
102. Na S, Li B, Grewal IS, Enslen H, Davis RJ, et al. (1999) Expression of activated CDC42 induces T cell apoptosis in thymus and peripheral lymph organs via different pathways. Oncogene 18:7966-7974.
103. Bustelo XR (2002) Understanding Rho/Rac biology in T-cells using animal models. Bioessays 24:602-612.
104. Cantrell DA (2003) GTPases and T cell activation. Immunol Rev 192: 122-130.
105. Corre I, Gomez M, Vielkind S, Cantrell DA (2001) Analysis of thymocyte development reveals that the GTPase RhoA is a positive regulator of T cell receptor responses in vivo. J Exp Med 194:903-914.
106. Dumont C, Corsoni-Tadrzak A, Ruf S, de Boer J, Williams A, et al. (2009) Rac GTPases play critical roles in early T-cell development. Blood 113: 3990-3998.
107. Yu H, Leitenberg D, Li B, Flavell RA (2001) Deficiency of small GTPase Rac2 affects T cell activation. J Exp Med 194:915-926.
108. Li B, Yu H, Zheng W, Voll R, Na S, et al. (2000) Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science 288: 2219-2222.
109. Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, et al. (2007) RhoH is important for.positive thymocyte selection and T-cell receptor signaling. Blood 109:2346-2355.
110. Guo F, Cancelas JA, Hildeman D, Williams DA, Zheng Y (2008) Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development. Blood 112:1767-1775.
111. Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, et al. (2006) RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol 7:1182-1190.
112. Vincent S, Jeanteur P, Fort P (1992) Growth-regulated expression of rhoG, a new member of the ras homolog gene family. Mol Cell Biol 12:3138-3148.
113. Vigorito E, Billadeu DD, Savoy D, McAdam S, Doody G, et al. (2003) RhoG regulates gene expression and the actin cytoskeleton in lymphocytes. Oncogene 22:330-342.
114. Guo F, Velu CS, Grimes HL, Zheng Y (2009) Rho GTPase Cdc42 is essential for B-lymphocyte development and activation. Blood 114: 2909-2916.
115. Bokoch GM (2005) Regulation of innate immunity by Rho GTPases. Trends Cell Biol 15:163-171.
116. Dinauer MC (2003) Regulation of neutrophil function by Rac GTPases. Curr Opin Hematol 10:8-15.
117. Gu Y, Jia B, Yang FC, D'Souza M, Harris CE, et al. (2001) Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency. J Biol Chem 276:15929-15938.
118. Zhang X, Shang X, Guo F, Murphy K, Kirby M, et al. (2008) Defective homing is associated with altered Cdc42 activity in cells from patients with Fanconi anemia group A. Blood 112:1683-1686.
119. Haneline LS, Gobbett TA, Ramani R, Carreau M, Buchwald M, et al. (1999) Loss of FancC function results in decreased hematopoietic stem cell repopulating ability. Blood 94:1-8.
120. Sejas DP, Rani R, Qiu Y, Zhang X, Fagerlie SR, et al. (2007) Inflammatory reactive oxygen species-mediated hemopoietic suppression in Fancc-deficient mice. J Immunol 178:5277-5287.
121. Haneline LS, Broxmeyer HE, Cooper S, Hangoc G, Carreau M, et al. (1998) Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac-/-mice. Blood 91:4092-4098.
122. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, et al. (2001) Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412:341-346.
123. Preudhomme C, Roumier C, Hildebrand MP, Dallery-Prudhomme E, Lantoine D, et al. (2000) Nonrandom 4p13 rearrangements of the RhoH/TTF gene, encoding a GTP-binding protein, in non-Hodgkin's lymphoma and multiple myeloma. Oncogene 19:2023-2032.
124. Cherry LK, Li X, Schwab P, Lim B, Klickstein LB (2004) RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes. Nat Immunol 5:961-967.
125. Sanchez-Aguilera A, Rattmann I, Drew DZ, Muller LU, Summey V, et al. (2010) Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia. Leukemia 24:97-104.
126. Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS (2008) Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res 68: 4531-4540.
127. Thomas EK, Cancelas JA, Zheng Y, Williams DA (2008) Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis. Leukemia 22: 898-904.
128. Cho YJ, Zhang B, Kaartinen V, Haataja L, de Curtis I, et al. (2005) Generation of rac3 null mutant mice:role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia. Mol Cell Biol 25:5777-5785.
129. Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, et al. (2000) Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor:evidence for its fusion with MLL in acute myeloid leukemia. Proc Natl Acad Sci U S A 97:2145-2150.
130. Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, et al. (2001) Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. J Biol Chem 276:27145-27151.
131. Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, et al. (2000) The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q. Proc Natl Acad Sci U S A 97: 9168-9173.
132. Bojesen SE, Ammerpohl O, Weinhausl A, Haas OA, Mettal H, et al. (2006) Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome. Br J Cancer 94:323-332.
133. Somervaille TC, Cleary ML (2006) Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10:257-268.
134. Wei J, Wunderlich M, Fox C, Alvarez S, Cigudosa JC, et al. (2008) Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13:483-495.
135. Rozenveld-Geugien M, Baas IO, van Gosliga D, Vellenga E, Schuringa JJ (2007) Expansion of normal and leukemic human hematopoietic stem/progenitor cells requires rac-mediated interaction with stromal cells. Exp Hematol 35:782-792.
136. Fackler OT, Luo W, Geyer M, Alberts AS, Peterlin BM (1999) Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions. Mol Cell 3:729-739.
137. del Real G, Jimenez-Baranda S, Mira E, Lacalle RA, Lucas P, et al. (2004) Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med 200:541-547.
138. Madureira PA, Matos P, Soeiro I, Dixon LK, Simas JP, et al. (2005) Murine gamma-herpesvirus 68 latency protein M2 binds to Vav signaling proteins and inhibits B-cell receptor-induced cell cycle arrest and apoptosis in WEHI-231 B cells. J Biol Chem 280:37310-37318.
139. Rodrigues L, Pires de Miranda M, Caloca MJ, Bustelo XR, Simas JP (2006) Activation of Vav by the gammaherpesvirus M2 protein contributes to the establishment of viral latency in B lymphocytes. J Virol 80:6123-6135.
2. Wolf NS (1979) The haemopoietic microenvironment. Clin Haematol 8:469-500.
3. Dexter TM (1982) Stromal cell associated haemopoiesis. J Cell Physiol Suppl 1:87-94.
4. Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4:7-25.
5. Zhu J, Emerson SG (2004) A new bone to pick:osteoblasts and the haematopoietic stem-cell niche. Bioessays 26:595-599.
6. Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family: regulation, effectors and functions in vivo. Bioessays 29:356-370.
7. Caussinus E, Gonzalez C (2005) Induction of tumor growth by altered stem-cell asymmetric division in Drosophila melanogaster. Nat Genet 37:1125-1129.
8. Rossman KL, Der CJ, Sondek J (2005) GEF means go:turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6:167-180.
9. Peck J, Douglas Gt, Wu CH, Burbelo PD (2002) Human RhoGAP domain-containing proteins:structure, function and evolutionary relationships. FEBS Lett 528:27-34.
10. Winter-Vann AM, Casey PJ (2005) Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer 5:405-412.
11. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629-635.
12. Theriault BL, Shepherd TG, Mujoomdar ML, Nachtigal MW (2007) BMP4 induces EMT and Rho GTPase activation in human ovarian cancer cells. Carcinogenesis 28: 1153-1162.
13. Patel V, Rosenfeldt HM, Lyons R, Servitja JM, Bustelo XR, et al. (2007) Persistent activation of Rac1 in squamous carcinomas of the head and neck:evidence for an EGFR/Vav2 signaling axis involved in cell invasion. Carcinogenesis 28:1145-1152.
14. Pan ZZ, Bruening W, Godwin AK (2006) Involvement of RHO GTPases and ERK in synuclein-gamma enhanced cancer cell motility. Int J Oncol 29:1201-1205.
15. Merajver SD, Usmani SZ (2005) Multifaceted role of Rho proteins in angiogenesis. J Mammary Gland Biol Neoplasia 10:291-298.
16. Fukui K, Tamura S, Wada A, Kamada Y, Sawai Y, et al. (2006) Expression and prognostic role of RhoA GTPases in hepatocellular carcinoma. J Cancer Res Clin Oncol 132: 627-633.
17. Hall A (1998) Rho GTPases and the actin cytoskeleton. Science 279:509-514.
18. Jaffe AB, Hall A (2005) Rho GTPases:biochemistry and biology. Annu Rev Cell Dev Biol 21:247-269.
19. Wang J, Rao Q, Wang M, Wei H, Xing H, et al. (2009) Overexpression of Rac1 in leukemia patients and its role in leukemia cell migration and growth. Biochem Biophys Res Commun 386:769-774.
20. Brabletz T, Jung A, Spaderna S, Hlubek F, Kirchner T (2005) Opinion:migrating cancer stem cells-an integrated concept of malignant tumour progression. Nat Rev Cancer 5: 744-749.
21. Cherry LK, Li X, Schwab P, Lim B, Klickstein LB (2004) RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes. Nat Immunol 5:961-967.
22. Sanchez-Aguilera A, Rattmann I, Drew DZ, Muller LU, Summey V, et al. (2010) Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia. Leukemia 24:97-104.
23. Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, et al. (2000) Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor:evidence for its fusion with MLL in acute myeloid leukemia. Proc Natl Acad Sci U S A 97:2145-2150.
24. Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, et al. (2001) Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. J Biol Chem 276: 27145-27151.
25. Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, et al. (2000) The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q. Proc Natl Acad Sci U S A 97:9168-9173.
26. Bojesen SE, Ammerpohl O, Weinhausl A, Haas OA, Mettal H, et al. (2006) Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome. Br J Cancer 94:323-332.
27. Cleverley SC, Costello PS, Henning SW, Cantrell DA (2000) Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma. Oncogene 19:13-20.
28. Wei J, Wunderlich M, Fox C, Alvarez S, Cigudosa JC, et al. (2008) Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13: 483-495.
29. Yang FC, Atkinson SJ, Gu Y, Borneo JB, Roberts AW, et al. (2001) Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization. Proc Natl Acad Sci U S A 98:5614-5618.
1. Bustelo XR, Sauzeau V, Berenjeno IM (2007) GTP-binding proteins of the Rho/Rac family:regulation, effectors and functions in vivo. Bioessays 29: 356-370.
2. Rossman KL, Der CJ, Sondek J (2005) GEF means go:turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6: 167-180.
3. Peck J, Douglas Gt, Wu CH, Burbelo PD (2002) Human RhoGAP domain-containing proteins:structure, function and evolutionary relationships. FEBS Lett 528:27-34.
4. Winter-Vann AM, Casey PJ (2005) Post-prenylation-processing enzymes as new targets in oncogenesis. Nat Rev Cancer 5:405-412.
5. Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, et al. (1999) Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science 285:895-898.
6. Pollard TD, Blanchoin L, Mullins RD (2000) Molecular mechanisms controlling actin filament dynamics in nonmuscle cells. Annu Rev Biophys Biomol Struct 29:545-576.
7. Ishizaki T, Morishima Y, Okamoto M, Furuyashiki T, Kato T, et al. (2001) Coordination of microtubules and the actin cytoskeleton by the Rho effector mDia1. Nat Cell Biol 3:8-14.
8. Stephens L, Ellson C, Hawkins P (2002) Roles of PI3Ks in leukocyte chemotaxis and phagocytosis. Curr Opin Cell Biol 14:203-213.
9. Etienne-Manneville S, Hall A (2001) Integrin-mediated activation of Cdc42 controls cell polarity in migrating astrocytes through PKCzeta. Cell 106: 489-498.
10. Tanegashima K, Zhao H, Dawid IB (2008) WGEF activates Rho in the Wnt-PCP pathway and controls convergent extension in Xenopus gastrulation. EMBO J 27:606-617.
11. Kovar DR (2006) Molecular details of formin-mediated actin assembly. Curr Opin Cell Biol 18:11-17.
12. Liu W, Sato A, Khadka D, Bharti R, Diaz H, et al. (2008) Mechanism of activation of the Formin protein Daam1. Proc Natl Acad Sci U S A 105: 210-215.
13. Lu J, Meng W, Poy F, Maiti S, Goode BL, et al. (2007) Structure of the FH2 domain of Daam1:implications for formin regulation of actin assembly. J Mol Biol 369:1258-1269.
14. Aspenstrom P, Richnau N, Johansson AS (2006) The diaphanous-related formin DAAM1 collaborates with the Rho GTPases RhoA and Cdc42, CIP4 and Src in regulating cell morphogenesis and actin dynamics. Exp Cell Res 312:2180-2194.
15. Jaffe AB, Hall A (2005) Rho GTPases:biochemistry and biology. Annu Rev Cell Dev Biol 21:247-269.
16. Takaishi K, Sasaki T, Kotani H, Nishioka H, Takai Y (1997) Regulation of cell-cell adhesion by rac and rho small G proteins in MDCK cells. J Cell Biol 139:1047-1059.
17. Braga VM, Machesky LM, Hall A, Hotchin NA (1997) The small GTPases Rho and Rac are required for the establishment of cadherin-dependent cell-cell contacts. J Cell Biol 137:1421-1431.
18. Boureux A, Vignal E, Faure S, Fort P (2007) Evolution of the Rho family of ras-like GTPases in eukaryotes. Mol Biol Evol 24:203-216.
19. Katoh H, Negishi M (2003) RhoG activates Rac1 by direct interaction with the Dock180-binding protein Elmo. Nature 424:461-464.
20. Ridley AJ (2001) Rho GTPases and cell migration. J Cell Sci 114: 2713-2722.
21. Wells CM, Walmsley M, Ooi S, Tybulewicz V, Ridley AJ (2004) Rac1-deficient macrophages exhibit defects in cell spreading and membrane ruffling but not migration. J Cell Sci 117:1259-1268.
22. Sun CX, Downey GP, Zhu F, Koh AL, Thang H, et al. (2004) Rac1 is the small GTPase responsible for regulating the neutrophil chemotaxis compass. Blood 104:3758-3765.
23. Roberts AW, Kim C, Zhen L, Lowe JB, Kapur R, et al. (1999) Deficiency of the hematopoietic cell-specific Rho family GTPase Rac2 is characterized by abnormalities in neutrophil function and host defense. Immunity 10: 183-196.
24. Takenawa T, Suetsugu S (2007) The WASP-WAVE protein network: connecting the membrane to the cytoskeleton. Nat Rev Mol Cell Biol 8: 37-48.
25. Wang W, Eddy R, Condeelis J (2007) The cofilin pathway in breast cancer invasion and metastasis. Nat Rev Cancer 7:429-440.
26. Sun CX, Magalhaes MA, Glogauer M (2007) Rac1 and Rac2 differentially regulate actin free barbed end formation downstream of the fMLP receptor. J Cell Biol 179:239-245.
27. Yamauchi A, Kim C, Li S, Marchal CC, Towe J, et al. (2004) Rac2-deficient murine macrophages have selective defects in superoxide production and phagocytosis of opsonized particles. J Immunol 173:5971-5979.
28. Gupton SL, Gertler FB (2007) Filopodia:the fingers that do the walking. Sci STKE 2007:re5.
29. Chen F, Ma L, Parrini MC, Mao X, Lopez M, et al. (2000) Cdc42 is required for PIP(2)-induced actin polymerization and early development but not for cell viability. Curr Biol 10:758-765.
30. Garvalov BK, Flynn KC, Neukirchen D, Meyn L, Teusch N, et al. (2007) Cdc42 regulates cofilin during the establishment of neuronal polarity. J Neurosci27:13117-13129.
31. Yang L, Wang L, Zheng Y (2006) Gene targeting of Cdc42 and Cdc42GAP affirms the critical involvement of Cdc42 in filopodia induction, directed migration, and proliferation in primary mouse embryonic fibroblasts. Mol Biol Cell 17:4675-4685.
32. Czuchra A, Wu X, Meyer H, van Hengel J, Schroeder T, et al. (2005) Cdc42 is not essential for filopodium formation, directed migration, cell polarization, and mitosis in fibroblastoid cells. Mol Biol Cell 16:4473-4484.
33. Garcia-Bernal D, Wright N, Sotillo-Mallo E, Nombela-Arrieta C, Stein JV, et al. (2005) Vav1 and Rac control chemokine-promoted T lymphocyte adhesion mediated by the integrin alpha4beta1. Mol Biol Cell 16:3223-3235.
34. Pradip D, Peng X, Durden DL (2003) Rac2 specificity in macrophage integrin signaling:potential role for Syk kinase. J Biol Chem 278:41661-41669.
35. Yang FC, Atkinson SJ, Gu Y, Borneo JB, Roberts AW, et al. (2001) Rac and Cdc42 GTPases control hematopoietic stem cell shape, adhesion, migration, and mobilization. Proc Natl Acad Sci U S A 98:5614-5618.
36. Jansen M, Yang FC, Cancelas JA, Bailey JR, Williams DA (2005) Rac2-deficient hematopoietic stem cells show defective interaction with the hematopoietic microenvironment and long-term engraftment failure. Stem Cells 23:335-346.
37. Gu Y, Filippi MD, Cancelas JA, Siefring JE, Williams EP, et al. (2003) Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases. Science 302:445-449.
38. Cancelas JA, Lee AW, Prabhakar R, Stringer KF, Zheng Y, et al. (2005) Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization. Nat Med 11:886-891.
39. Motegi F, Sugimoto A (2006) Sequential functioning of the ECT-2 RhoGEF, RHO-1 and CDC-42 establishes cell polarity in Caenorhabditis elegans embryos. Nat Cell Biol 8:978-985.
40. Rojas R, Ruiz WG, Leung SM, Jou TS, Apodaca G (2001) Cdc42-dependent modulation of tight junctions and membrane protein traffic in polarized Madin-Darby canine kidney cells. Mol Biol Cell 12:2257-2274.
41. Yang L, Wang L, Geiger H, Cancelas JA, Mo J, et al. (2007) Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow. Proc Natl Acad Sci U S A 104:5091-5096.
42. Cappello S, Attardo A, Wu X, Iwasato T, Itohara S, et al. (2006) The Rho-GTPase cdc42 regulates neural progenitor fate at the apical surface. Nat Neurosci 9:1099-1107.
43. Chen L, Liao G, Yang L, Campbell K, Nakafuku M, et al. (2006) Cdc42 deficiency causes Sonic hedgehog-independent holoprosencephaly. Proc Natl Acad Sci U S A 103:16520-16525.
44. Watabe-Uchida M, Govek EE, Van Aelst L (2006) Regulators of Rho GTPases in neuronal development. J Neurosci 26:10633-10635.
45. Benitah SA, Frye M, Glogauer M, Watt FM (2005) Stem cell depletion through epidermal deletion of Rac1. Science 309:933-935.
46. Stramer B, Wood W, Galko MJ, Redd MJ, Jacinto A, et al. (2005) Live imaging of wound inflammation in Drosophila embryos reveals key roles for small GTPases during in vivo cell migration. J Cell Biol 168:567-573.
47. Srinivasan S, Wang F, Glavas S, Ott A, Hofmann F, et al. (2003) Rac and Cdc42 play distinct roles in regulating PI(3,4,5)P3 and polarity during neutrophil chemotaxis. J Cell Biol 160:375-385.
48. Szczur K, Xu H, Atkinson S, Zheng Y, Filippi MD (2006) Rho GTPase CDC42 regulates directionality and random movement via distinct MAPK pathways in neutrophils. Blood 108:4205-4213.
49. Wu X, Quondamatteo F, Lefever T, Czuchra A, Meyer H, et al. (2006) Cdc42 controls progenitor cell differentiation and beta-catenin turnover in skin. Genes Dev 20:571-585.
50. Yang L, Wang L, Kalfa TA, Cancelas JA, Shang X, et al. (2007) Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis. Blood 110:3853-3861.
51. Chimini G, Chavrier P (2000) Function of Rho family proteins in actin dynamics during phagocytosis and engulfment. Nat Cell Biol 2:E191-196.
52. Koh AL, Sun CX, Zhu F, Glogauer M (2005) The role of Rac1 and Rac2 in bacterial killing. Cell Immunol 235:92-97.
53. Williams DA, Tao W, Yang F, Kim C, Gu Y, et al. (2000) Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency. Blood 96:1646-1654.
54. Hoppe AD, Swanson JA (2004) Cdc42, Rac1, and Rac2 display distinct patterns of activation during phagocytosis. Mol Biol Cell 15:3509-3519.
55. Hall AB, Gakidis MA, Glogauer M, Wilsbacher JL, Gao S, et al. (2006) Requirements for Vav guanine nucleotide exchange factors and Rho GTPases in FcgammaR-and complement-mediated phagocytosis. Immunity 24:305-316.
56. Govek EE, Newey SE, Van Aelst L (2005) The role of the Rho GTPases in neuronal development. Genes Dev 19:1-49.
57. Chen TJ, Gehler S, Shaw AE, Bamburg JR, Letourneau PC (2006) Cdc42 participates in the regulation of ADF/cofilin and retinal growth cone filopodia by brain derived neurotrophic factor. J Neurobiol 66:103-114.
58. Koh CG (2006) Rho GTPases and their regulators in neuronal functions and development. Neurosignals 15:228-237.
59. Threadgill R, Bobb K, Ghosh A (1997) Regulation of dendritic growth and remodeling by Rho, Rac, and Cdc42. Neuron 19:625-634.
60. Albertinazzi C, Gilardelli D, Paris S, Longhi R, de Curtis (?).(1998) Overexpression of a neural-specific rho family GTPase, cRac1B, selectively induces enhanced neuritogenesis and neurite branching in primary neurons. J Cell Biol 142:815-825.
61. Corbetta S, Gualdoni S, Albertinazzi C, Paris S, Croci L, et al. (2005) Generation and characterization of Rac3 knockout mice. Mol Cell Biol 25: 5763-5776.
62. Gualdoni S, Albertinazzi C, Corbetta S, Valtorta F, de Curtis I (2007) Normal levels of Rac1 are important for dendritic but not axonal development in hippocampal neurons. Biol Cell 99:455-464.
63. Etienne-Manneville S, Hall A (2002) Rho GTPases in cell biology. Nature 420:629-635.
64. Lane J, Martin TA, Mansel RE, Jiang WG (2008) The expression and prognostic value of the guanine nucleotide exchange factors (GEFs) Trio, Vav1 and TIAM-1 in human breast cancer. Int Semin Surg Oncol 5:23.
65. Fukui K, Tamura S, Wada A, Kamada Y, Sawai Y, et al. (2006) Expression and prognostic role of RhoA GTPases in hepatocellular carcinoma. J Cancer Res Clin Oncol 132:627-633.
66. Li XR, Ji F, Ouyang J, Wu W, Qian LY, et al. (2006) Overexpression of RhoA is associated with poor prognosis in hepatocellular carcinoma. Eur J Surg Oncol 32:1130-1134.
67. Abraham MT, Kuriakose MA, Sacks PG, Yee H, Chiriboga L, et al. (2001) Motility-related proteins as markers for head and neck squamous cell cancer. Laryngoscope 111:1285-1289.
68. Adnane J, Seijo E, Chen Z, Bizouarn F, Leal M, et al. (2002) RhoB, not RhoA, represses the transcription of the transforming growth factor beta type II receptor by a mechanism involving activator protein 1. J Biol Chem 277: 8500-8507.
69. Fritz G, Just I, Kaina B (1999) Rho GTPases are over-expressed in human tumors. Int J Cancer 81:682-687.
70. Horiuchi A, Imai T, Wang C, Ohira S, Feng Y, et al. (2003) Up-regulation of small GTPases, RhoA and RhoC, is associated with tumor progression in ovarian carcinoma. Lab Invest 83:861-870.
71. Kamai T, Tsujii T, Arai K, Takagi K, Asami H, et al. (2003) Significant association of Rho/ROCK pathway with invasion and metastasis of bladder cancer. Clin Cancer Res 9:2632-2641.
72. Pan Y, Bi F, Liu N, Xue Y, Yao X, et al. (2004) Expression of seven main Rho family members in gastric carcinoma. Biochem Biophys Res Commun 315:686-691.
73. Faried A, Faried LS, Usman N, Kato H, Kuwano H (2007) Clinical and prognostic significance of RhoA and RhoC gene expression in esophageal squamous cell carcinoma. Ann Surg Oncol 14:3593-3601.
74. Kamai T, Yamanishi T, Shirataki H, Takagi K, Asami H, et al. (2004) Overexpression of RhoA, Rac1, and Cdc42 GTPases is associated with progression in testicular cancer. Clin Cancer Res 10:4799-4805.
75. Wheeler AP, Ridley AJ (2004) Why three Rho proteins? RhoA, RhoB, RhoC, and cell motility. Exp Cell Res 301:43-49.
76. Henning SW, Galandrini R, Hall A, Cantrell DA (1997) The GTPase Rho has a critical regulatory role in thymus development. EMBO J 16:2397-2407.
77. Cleverley SC, Costello PS, Henning SW, Cantrell DA (2000) Loss of Rho function in the thymus is accompanied by the development of thymic lymphoma. Oncogene 19:13-20.
78. Horiuchi A, Kikuchi N, Osada R, Wang C, Hayashi A, et al. (2008) Overexpression of RhoA enhances peritoneal dissemination:RhoA suppression with Lovastatin may be useful for ovarian cancer. Cancer Sci 99: 2532-2539.
79. Schnelzer A, Prechtel D, Knaus U, Dehne K, Gerhard M, et al. (2000) Rac1 in human breast cancer:overexpression, mutation analysis, and characterization of a new isoform, Rac1b. Oncogene 19:3013-3020.
80. Liu SY, Yen CY, Yang SC, Chiang WF, Chang KW (2004) Overexpression of Rac-1 small GTPase binding protein in oral squamous cell carcinoma. J Oral Maxillofac Surg 62:702-707.
81. Espina C, Cespedes MV, Garcia-Cabezas MA, Gomez del Pulgar MT, Boluda A, et al. (2008) A critical role for Rac1 in tumor progression of human colorectal adenocarcinoma cells. Am J Pathol 172:156-166.
82. Kissil JL, Walmsley MJ, Hanlon L, Haigis KM, Bender Kim CF, et al. (2007) Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res 67:8089-8094.
83. Harnois T, Constantin B, Rioux A, Grenioux E, Kitzis A, et al. (2003) Differential interaction and activation of Rho family GTPases by p210bcr-abl and p190bcr-abl. Oncogene 22:6445-6454.
84. Thomas EK, Cancelas JA, Chae HD, Cox AD, Keller PJ, et al. (2007) Rac guanosine triphosphatases represent integrating molecular therapeutic targets for BCR-ABL-induced myeloproliferative disease. Cancer Cell 12: 467-478.
85. van Hengel J, D'Hooge P, Hooghe B, Wu X, Libbrecht L, et al. (2008) Continuous cell injury promotes hepatic tumorigenesis in cdc42-deficient mouse liver. Gastroenterology 134:781-792.
86. Schofield R (1978) The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells 4:7-25.
87. Kiel MJ, Morrison SJ (2008) Uncertainty in the niches that maintain haematopoietic stem cells. Nat Rev Immunol 8:290-301.
88. Tan BL, Yazicioglu MN, Ingram D, McCarthy J, Borneo J, et al. (2003) Genetic evidence for convergence of c-Kit-and alpha4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells. Blood 101:4725-4732.
89. del Pozo MA, Vicente-Manzanares M, Tejedor R, Serrador JM, Sanchez-Madrid F (1999) Rho GTPases control migration and polarization of adhesion molecules and cytoskeletal ERM components in T lymphocytes. Eur J Immunol 29:3609-3620.
90. Ghiaur G, Ferkowicz MJ, Milsom MD, Bailey J, Witte D, et al. (2008) Rac1 is essential for intraembryonic hematopoiesis and for the initial seeding of fetal liver with definitive hematopoietic progenitor cells. Blood 111:3313-3321.
91. Wang L, Yang L, Filippi MD, Williams DA, Zheng Y (2006) Genetic deletion of Cdc42GAP reveals a role of Cdc42 in erythropoiesis and hematopoietic stem/progenitor cell survival, adhesion, and engraftment. Blood 107:98-105.
92. Xing Z, Ryan MA, Daria D, Nattamai KJ, Van Zant G, et al. (2006) Increased hematopoietic stem cell mobilization in aged mice. Blood 108:2190-2197.
93. Williams DA, Cancelas JA (2006) Leukaemia:niche retreats for stem cells. Nature 444:827-828.
94. Kondo M, Weissman IL, Akashi K (1997) Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91:661-672.
95. Akashi K, Traver D, Miyamoto T, Weissman IL (2000) A clonogenic common myeloid progenitor that gives rise to all myeloid lineages. Nature 404: 193-197.
96. Gao Y, Dickerson JB, Guo F, Zheng J, Zheng Y (2004) Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A 101:7618-7623.
97. Ji P, Jayapal SR, Lodish HF (2008) Enucleation of cultured mouse fetal erythroblasts requires Rac GTPases and mDia2. Nat Cell Biol 10:314-321.
98. Kalfa TA, Pushkaran S, Mohandas N, Hartwig JH, Fowler VM, et al. (2006) Rac GTPases regulate the morphology and deformability of the erythrocyte cytoskeleton. Blood 108:3637-3645.
99. Borroto A, Gil D, Delgado P, Vicente-Manzanares M, Alcover A, et al. (2000) Rho regulates T cell receptor ITAM-induced lymphocyte spreading in an integrin-independent manner. Eur J Immunol 30:3403-3410.
100. Campbell KS (1999) Signal transduction from the B cell antigen-receptor. Curr Opin Immunol 11:256-264.
101. Gomez M, Tybulewicz V, Cantrell DA (2000) Control of pre-T cell proliferation and differentiation by the GTPase Rac-I. Nat Immunol 1: 348-352.
102. Na S, Li B, Grewal IS, Enslen H, Davis RJ, et al. (1999) Expression of activated CDC42 induces T cell apoptosis in thymus and peripheral lymph organs via different pathways. Oncogene 18:7966-7974.
103. Bustelo XR (2002) Understanding Rho/Rac biology in T-cells using animal models. Bioessays 24:602-612.
104. Cantrell DA (2003) GTPases and T cell activation. Immunol Rev 192: 122-130.
105. Corre I, Gomez M, Vielkind S, Cantrell DA (2001) Analysis of thymocyte development reveals that the GTPase RhoA is a positive regulator of T cell receptor responses in vivo. J Exp Med 194:903-914.
106. Dumont C, Corsoni-Tadrzak A, Ruf S, de Boer J, Williams A, et al. (2009) Rac GTPases play critical roles in early T-cell development. Blood 113: 3990-3998.
107. Yu H, Leitenberg D, Li B, Flavell RA (2001) Deficiency of small GTPase Rac2 affects T cell activation. J Exp Med 194:915-926.
108. Li B, Yu H, Zheng W, Voll R, Na S, et al. (2000) Role of the guanosine triphosphatase Rac2 in T helper 1 cell differentiation. Science 288: 2219-2222.
109. Dorn T, Kuhn U, Bungartz G, Stiller S, Bauer M, et al. (2007) RhoH is important for.positive thymocyte selection and T-cell receptor signaling. Blood 109:2346-2355.
110. Guo F, Cancelas JA, Hildeman D, Williams DA, Zheng Y (2008) Rac GTPase isoforms Rac1 and Rac2 play a redundant and crucial role in T-cell development. Blood 112:1767-1775.
111. Gu Y, Chae HD, Siefring JE, Jasti AC, Hildeman DA, et al. (2006) RhoH GTPase recruits and activates Zap70 required for T cell receptor signaling and thymocyte development. Nat Immunol 7:1182-1190.
112. Vincent S, Jeanteur P, Fort P (1992) Growth-regulated expression of rhoG, a new member of the ras homolog gene family. Mol Cell Biol 12:3138-3148.
113. Vigorito E, Billadeu DD, Savoy D, McAdam S, Doody G, et al. (2003) RhoG regulates gene expression and the actin cytoskeleton in lymphocytes. Oncogene 22:330-342.
114. Guo F, Velu CS, Grimes HL, Zheng Y (2009) Rho GTPase Cdc42 is essential for B-lymphocyte development and activation. Blood 114: 2909-2916.
115. Bokoch GM (2005) Regulation of innate immunity by Rho GTPases. Trends Cell Biol 15:163-171.
116. Dinauer MC (2003) Regulation of neutrophil function by Rac GTPases. Curr Opin Hematol 10:8-15.
117. Gu Y, Jia B, Yang FC, D'Souza M, Harris CE, et al. (2001) Biochemical and biological characterization of a human Rac2 GTPase mutant associated with phagocytic immunodeficiency. J Biol Chem 276:15929-15938.
118. Zhang X, Shang X, Guo F, Murphy K, Kirby M, et al. (2008) Defective homing is associated with altered Cdc42 activity in cells from patients with Fanconi anemia group A. Blood 112:1683-1686.
119. Haneline LS, Gobbett TA, Ramani R, Carreau M, Buchwald M, et al. (1999) Loss of FancC function results in decreased hematopoietic stem cell repopulating ability. Blood 94:1-8.
120. Sejas DP, Rani R, Qiu Y, Zhang X, Fagerlie SR, et al. (2007) Inflammatory reactive oxygen species-mediated hemopoietic suppression in Fancc-deficient mice. J Immunol 178:5277-5287.
121. Haneline LS, Broxmeyer HE, Cooper S, Hangoc G, Carreau M, et al. (1998) Multiple inhibitory cytokines induce deregulated progenitor growth and apoptosis in hematopoietic cells from Fac-/-mice. Blood 91:4092-4098.
122. Pasqualucci L, Neumeister P, Goossens T, Nanjangud G, Chaganti RS, et al. (2001) Hypermutation of multiple proto-oncogenes in B-cell diffuse large-cell lymphomas. Nature 412:341-346.
123. Preudhomme C, Roumier C, Hildebrand MP, Dallery-Prudhomme E, Lantoine D, et al. (2000) Nonrandom 4p13 rearrangements of the RhoH/TTF gene, encoding a GTP-binding protein, in non-Hodgkin's lymphoma and multiple myeloma. Oncogene 19:2023-2032.
124. Cherry LK, Li X, Schwab P, Lim B, Klickstein LB (2004) RhoH is required to maintain the integrin LFA-1 in a nonadhesive state on lymphocytes. Nat Immunol 5:961-967.
125. Sanchez-Aguilera A, Rattmann I, Drew DZ, Muller LU, Summey V, et al. (2010) Involvement of RhoH GTPase in the development of B-cell chronic lymphocytic leukemia. Leukemia 24:97-104.
126. Galiegue-Zouitina S, Delestre L, Dupont C, Troussard X, Shelley CS (2008) Underexpression of RhoH in Hairy Cell Leukemia. Cancer Res 68: 4531-4540.
127. Thomas EK, Cancelas JA, Zheng Y, Williams DA (2008) Rac GTPases as key regulators of p210-BCR-ABL-dependent leukemogenesis. Leukemia 22: 898-904.
128. Cho YJ, Zhang B, Kaartinen V, Haataja L, de Curtis I, et al. (2005) Generation of rac3 null mutant mice:role of Rac3 in Bcr/Abl-caused lymphoblastic leukemia. Mol Cell Biol 25:5777-5785.
129. Kourlas PJ, Strout MP, Becknell B, Veronese ML, Croce CM, et al. (2000) Identification of a gene at 11q23 encoding a guanine nucleotide exchange factor:evidence for its fusion with MLL in acute myeloid leukemia. Proc Natl Acad Sci U S A 97:2145-2150.
130. Reuther GW, Lambert QT, Booden MA, Wennerberg K, Becknell B, et al. (2001) Leukemia-associated Rho guanine nucleotide exchange factor, a Dbl family protein found mutated in leukemia, causes transformation by activation of RhoA. J Biol Chem 276:27145-27151.
131. Borkhardt A, Bojesen S, Haas OA, Fuchs U, Bartelheimer D, et al. (2000) The human GRAF gene is fused to MLL in a unique t(5;11)(q31;q23) and both alleles are disrupted in three cases of myelodysplastic syndrome/acute myeloid leukemia with a deletion 5q. Proc Natl Acad Sci U S A 97: 9168-9173.
132. Bojesen SE, Ammerpohl O, Weinhausl A, Haas OA, Mettal H, et al. (2006) Characterisation of the GRAF gene promoter and its methylation in patients with acute myeloid leukaemia and myelodysplastic syndrome. Br J Cancer 94:323-332.
133. Somervaille TC, Cleary ML (2006) Identification and characterization of leukemia stem cells in murine MLL-AF9 acute myeloid leukemia. Cancer Cell 10:257-268.
134. Wei J, Wunderlich M, Fox C, Alvarez S, Cigudosa JC, et al. (2008) Microenvironment determines lineage fate in a human model of MLL-AF9 leukemia. Cancer Cell 13:483-495.
135. Rozenveld-Geugien M, Baas IO, van Gosliga D, Vellenga E, Schuringa JJ (2007) Expansion of normal and leukemic human hematopoietic stem/progenitor cells requires rac-mediated interaction with stromal cells. Exp Hematol 35:782-792.
136. Fackler OT, Luo W, Geyer M, Alberts AS, Peterlin BM (1999) Activation of Vav by Nef induces cytoskeletal rearrangements and downstream effector functions. Mol Cell 3:729-739.
137. del Real G, Jimenez-Baranda S, Mira E, Lacalle RA, Lucas P, et al. (2004) Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med 200:541-547.
138. Madureira PA, Matos P, Soeiro I, Dixon LK, Simas JP, et al. (2005) Murine gamma-herpesvirus 68 latency protein M2 binds to Vav signaling proteins and inhibits B-cell receptor-induced cell cycle arrest and apoptosis in WEHI-231 B cells. J Biol Chem 280:37310-37318.
139. Rodrigues L, Pires de Miranda M, Caloca MJ, Bustelo XR, Simas JP (2006) Activation of Vav by the gammaherpesvirus M2 protein contributes to the establishment of viral latency in B lymphocytes. J Virol 80:6123-6135.