蛋白酪氨酸磷酸酶SHP-2对佐剂性关节炎大鼠滑膜细胞中G蛋白偶联受体激酶2的作用及芍药苷对其的影响
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摘要
目的:
根据佐剂性关节炎(adjuvant arthritis,AA)大鼠的足爪肿胀、评分、关节滑膜及病理形态学等改变,观察芍药苷(paeoniflorin,Pae)对AA大鼠巨噬细胞分泌Il-1水平、T、B细胞增殖水平的影响;在整体、器官、细胞水平上明确Pae对AA大鼠的治疗作用;以AA发病的靶细胞—成纤维滑膜细胞(fibroblast-like synoviocytes,FLS)为突破口,观察Pae对AA大鼠FLS的增殖、cAMP水平、含有SH2结构域的酪氨酸蛋白磷酸酶( Src homology 2 domain-containing protein tyrosine phosphatase-2,SHP-2)、G蛋白偶联受体激酶2(G-protein-coupled receptor kinases 2,GRK_2)表达的影响;分析Pae是否通过影响SHP-2在AA大鼠FLS中的表达情况而发挥效应。明确SHP-2在FLS中调节GRK_2的作用及Pae治疗大鼠AA的可能的分子机制。
方法:
大鼠左后足跖皮内注射弗氏完全佐剂(Freund’s complete adjuvant,FCA)制备大鼠AA模型;以Pae(25、50、100 mg·kg~(-1))灌胃给药(intragastric administration, ig)(d14-d24)。计数法测定多发性关节炎指数,称重法测定脾脏指数, ELISA法检测巨噬细胞分泌IL-1水平,氚标记的胸腺嘧啶核苷掺入法测定T、B淋巴细胞增殖反应,HE染色法光镜观察关节病理形态学变化等。组织块法培养大鼠FLS,MTT法检测FLS的增殖反应;放射性免疫法测定FLS cAMP水平;Western blot技术检测FLS中GRK_2、SHP-2的表达变化。
结果:
1. Pae对AA大鼠的治疗作用
Pae(25、50、100 mg·kg~(-1))于造模后d14- d24灌胃给药均不同程度明显减轻AA大鼠多发性关节炎指数、继发侧肿胀度、升高的脾脏指数、升高的巨噬细胞分泌IL-1水平、增强的T、B淋巴细胞增殖反应及关节病理形态改变等方面都有不同程度的改善作用。光镜下观察关节滑膜组织中轻度的滑膜增生、淋巴细胞浸润减少;滑膜下有少量纤维增生、血管翳减轻;软骨受损程度减轻,仅见少量炎细胞;骨髓腔中脂肪细胞明显减少、骨骼细胞密集。充分显示了Pae对AA大鼠具有治疗作用。
2. SHP-2抑制剂NSC-87877对AA大鼠FLS增殖、胞内cAMP水平、GRK_2及SHP-2表达的影响
加入SHP-2抑制剂(NSC-87877)(10~(-5) mol·L~(-1))后,可显著抑制AA大鼠FLS的过度增殖,升高细胞内cAMP水平,降低AA大鼠FLS中GRK_2、SHP-2的高表达水平;分离FLS胞浆、胞膜蛋白,应用Western-blot方法,检测显示加入NSC-87877(10-5 mol·L~(-1))能显著降低AA大鼠FLS细胞膜中GRK_2蛋白的高表达水平,显著升高AA大鼠FLS细胞浆中GRK_2蛋白的低表达水平。
3. Pae对AA大鼠FLS增殖、胞内cAMP水平、GRK_2及SHP-2表达的影响
Pae(10~(-5)、10~(-6)、10~(-7)、10~(-8) mol·L~(-1))体外给药后,可显著抑制EP2受体激动剂(Butaprost)刺激的AA大鼠FLS的过度增殖,升高细胞内cAMP水平,降低AAWestern-blot方法,检测显示Pae(10~(-5)、10~(-6)、10~(-7)、10~(-8) mol·L~(-1))体外给药能显著降低AA大鼠FLS细胞膜中GRK_2蛋白的高表达水平,显著升高AA大鼠FLS细胞浆中GRK_2蛋白的低表达水平。
结论:
1、Pae对AA大鼠有一定的治疗的作用,对其多发性关节炎指数、升高的脾脏指数、继发侧肿胀度、升高的巨噬细胞分泌IL-1水平、增强的T、B淋巴细胞增殖反应及关节病理形态改变具有明显的改善作用。
2、SHP-2抑制剂可下调AA大鼠滑膜细胞GRK_2和SHP-2的高表达;降低细胞增殖水平,升高胞内cAMP水平;同时使胞膜GRK_2水平降低,而升高胞浆GRK_2水平。提示SHP-2可能促进了GRK_2的转膜,下调胞内cAMP水平,进而影响细胞增殖。
3、Pae(10~(-5)、10~(-6)、10(-7)、10~(-8) mol·L~(-1))体外给药,可不同程度地降低Butaprost刺激的AA大鼠FLS的异常增殖,下调SHP-2和GRK_2的高表达,提示下调SHP-2和GRK_2可能是Pae抑制FLS异常增殖的机制之一。
OBJECTIVE
According to the changes that secondary paw swelling, polyarthritis index,and histological morphological of adjuvant arthritis(AA)rats,this study tends to clarify the therapeutic effects of paeoniflorin(Pae) on AA rats.Meanwhile,our study aimed to confirm the role of GRK_2 and SHP-2 playing in fibroblase-like synoviocytes(FLS) of AA rats and the effects of Pae.And further to analyze mechanism of Pae on AA rats,we investigate the role of SHP-2 on GRK_2 and its signalling pathways.
METHODS
Freund's complete adjuvant (FCA)was used to induce AA in rats.Therapeutic treatment of interagastric administration Pae(12.5、25、50、100 mg·kg ~(-1)·d~(-1), d14-d24 )were given after immunization. Hind paw volumes of rats were measured by volume meter.Arthritis index,spleen index were recorded. IL-1 level produced by thymus T cells was measured by ELISA and the proliferation of T and B lymphocytes were measured by [3H]-TdR incorporation. Pathological changes in synovium of joint were observed by light microscope. The proliferation of fibroblase-likesynoviocytes was assayed using the MTT assay.cAMP were measured by radioimmunoassay.The expression of GRK_2、SHP-2 were detected by westernblot analysis.
RESULTS
1. therapeutic effects of Pae on AA rats
Pae(12.5、25、50、100 mg·kg ~(-1)·d~(-1), d14-d24) significantly suppressed significantly the paw swelling as well as down-regulated the index of polyarthritis、spleen index、IL-1 produced by thymus T cells and proliferation of T and B lymphocytes in AA rats. The articular histopathological changes were also improved.This suggested that Pae had therapeutic effects on AA rats.
2. Effects of SHP-2 inhibitor NSC-87877 on expression of GRK_2 and SHP-2、the level of cAMP、proliferation in synoviocytes from AA rats.
SHP-2 inhibitor NSC-87877 significantly inhibited proliferation of FLS、increased the level of cAMP in synoviocytes and decreased the expression of GRK_2、SHP-2 in FLS.The result of western blot analysis demonstrated that SHP-2 inhibitor NSC-87877(10~（-5）mol·L~(-1)) in vitro significantly decreased the expression of GRK_2 in membrane and increased GRK_2 in cytoplasm.
3. Effects of Pae on expression of GRK_2 and SHP-2、the level of cAMP、proliferation of FLS from AA rats.
Pae significantly inhibited proliferation of FLS、increased the level of cAMP in FLS and decreased the expression of GRK_2、SHP-2.The result of western blot analysis demonstrated that SHP-2 inhibitor NSC-87877(10~（-5）mol·L~(-1)) in vitro significantly decreased the expression of GRK_2 in membrane and increased GRK_2 in cytoplasm.
CONCLUSIONS
1. Pae could alleviate the inflammation of joint at different degree and decrease the spleen index ,the secretion of IL-1,proliferation of T,B lymphocyte and articular histopathological changes in rats with AA.
2. SHP-2 inhibitor could decrease the expression of GRK_2 and SHP-2 in FLS from AA rats; SHP-2 inhibitor inhibited proliferation of FLS by incpreasing the level of cAMP and improving the expresstion of GRK_2 in cytoplasm meanwhile decreased the expression of GRK_2 in membrane.Which indicated that SHP-2 inhibited proliferation of FLS by inhibiting transmembrane of GRK_2 and then increasing the level of cAMP in FLS.
3.Pae could decreased the expression of SHP-2 in FLS,which may be one of the important mechanisms for the Pae on AA rats.
根据佐剂性关节炎(adjuvant arthritis,AA)大鼠的足爪肿胀、评分、关节滑膜及病理形态学等改变,观察芍药苷(paeoniflorin,Pae)对AA大鼠巨噬细胞分泌Il-1水平、T、B细胞增殖水平的影响;在整体、器官、细胞水平上明确Pae对AA大鼠的治疗作用;以AA发病的靶细胞—成纤维滑膜细胞(fibroblast-like synoviocytes,FLS)为突破口,观察Pae对AA大鼠FLS的增殖、cAMP水平、含有SH2结构域的酪氨酸蛋白磷酸酶( Src homology 2 domain-containing protein tyrosine phosphatase-2,SHP-2)、G蛋白偶联受体激酶2(G-protein-coupled receptor kinases 2,GRK_2)表达的影响;分析Pae是否通过影响SHP-2在AA大鼠FLS中的表达情况而发挥效应。明确SHP-2在FLS中调节GRK_2的作用及Pae治疗大鼠AA的可能的分子机制。
方法:
大鼠左后足跖皮内注射弗氏完全佐剂(Freund’s complete adjuvant,FCA)制备大鼠AA模型;以Pae(25、50、100 mg·kg~(-1))灌胃给药(intragastric administration, ig)(d14-d24)。计数法测定多发性关节炎指数,称重法测定脾脏指数, ELISA法检测巨噬细胞分泌IL-1水平,氚标记的胸腺嘧啶核苷掺入法测定T、B淋巴细胞增殖反应,HE染色法光镜观察关节病理形态学变化等。组织块法培养大鼠FLS,MTT法检测FLS的增殖反应;放射性免疫法测定FLS cAMP水平;Western blot技术检测FLS中GRK_2、SHP-2的表达变化。
结果:
1. Pae对AA大鼠的治疗作用
Pae(25、50、100 mg·kg~(-1))于造模后d14- d24灌胃给药均不同程度明显减轻AA大鼠多发性关节炎指数、继发侧肿胀度、升高的脾脏指数、升高的巨噬细胞分泌IL-1水平、增强的T、B淋巴细胞增殖反应及关节病理形态改变等方面都有不同程度的改善作用。光镜下观察关节滑膜组织中轻度的滑膜增生、淋巴细胞浸润减少;滑膜下有少量纤维增生、血管翳减轻;软骨受损程度减轻,仅见少量炎细胞;骨髓腔中脂肪细胞明显减少、骨骼细胞密集。充分显示了Pae对AA大鼠具有治疗作用。
2. SHP-2抑制剂NSC-87877对AA大鼠FLS增殖、胞内cAMP水平、GRK_2及SHP-2表达的影响
加入SHP-2抑制剂(NSC-87877)(10~(-5) mol·L~(-1))后,可显著抑制AA大鼠FLS的过度增殖,升高细胞内cAMP水平,降低AA大鼠FLS中GRK_2、SHP-2的高表达水平;分离FLS胞浆、胞膜蛋白,应用Western-blot方法,检测显示加入NSC-87877(10-5 mol·L~(-1))能显著降低AA大鼠FLS细胞膜中GRK_2蛋白的高表达水平,显著升高AA大鼠FLS细胞浆中GRK_2蛋白的低表达水平。
3. Pae对AA大鼠FLS增殖、胞内cAMP水平、GRK_2及SHP-2表达的影响
Pae(10~(-5)、10~(-6)、10~(-7)、10~(-8) mol·L~(-1))体外给药后,可显著抑制EP2受体激动剂(Butaprost)刺激的AA大鼠FLS的过度增殖,升高细胞内cAMP水平,降低AAWestern-blot方法,检测显示Pae(10~(-5)、10~(-6)、10~(-7)、10~(-8) mol·L~(-1))体外给药能显著降低AA大鼠FLS细胞膜中GRK_2蛋白的高表达水平,显著升高AA大鼠FLS细胞浆中GRK_2蛋白的低表达水平。
结论:
1、Pae对AA大鼠有一定的治疗的作用,对其多发性关节炎指数、升高的脾脏指数、继发侧肿胀度、升高的巨噬细胞分泌IL-1水平、增强的T、B淋巴细胞增殖反应及关节病理形态改变具有明显的改善作用。
2、SHP-2抑制剂可下调AA大鼠滑膜细胞GRK_2和SHP-2的高表达;降低细胞增殖水平,升高胞内cAMP水平;同时使胞膜GRK_2水平降低,而升高胞浆GRK_2水平。提示SHP-2可能促进了GRK_2的转膜,下调胞内cAMP水平,进而影响细胞增殖。
3、Pae(10~(-5)、10~(-6)、10(-7)、10~(-8) mol·L~(-1))体外给药,可不同程度地降低Butaprost刺激的AA大鼠FLS的异常增殖,下调SHP-2和GRK_2的高表达,提示下调SHP-2和GRK_2可能是Pae抑制FLS异常增殖的机制之一。
OBJECTIVE
According to the changes that secondary paw swelling, polyarthritis index,and histological morphological of adjuvant arthritis(AA)rats,this study tends to clarify the therapeutic effects of paeoniflorin(Pae) on AA rats.Meanwhile,our study aimed to confirm the role of GRK_2 and SHP-2 playing in fibroblase-like synoviocytes(FLS) of AA rats and the effects of Pae.And further to analyze mechanism of Pae on AA rats,we investigate the role of SHP-2 on GRK_2 and its signalling pathways.
METHODS
Freund's complete adjuvant (FCA)was used to induce AA in rats.Therapeutic treatment of interagastric administration Pae(12.5、25、50、100 mg·kg ~(-1)·d~(-1), d14-d24 )were given after immunization. Hind paw volumes of rats were measured by volume meter.Arthritis index,spleen index were recorded. IL-1 level produced by thymus T cells was measured by ELISA and the proliferation of T and B lymphocytes were measured by [3H]-TdR incorporation. Pathological changes in synovium of joint were observed by light microscope. The proliferation of fibroblase-likesynoviocytes was assayed using the MTT assay.cAMP were measured by radioimmunoassay.The expression of GRK_2、SHP-2 were detected by westernblot analysis.
RESULTS
1. therapeutic effects of Pae on AA rats
Pae(12.5、25、50、100 mg·kg ~(-1)·d~(-1), d14-d24) significantly suppressed significantly the paw swelling as well as down-regulated the index of polyarthritis、spleen index、IL-1 produced by thymus T cells and proliferation of T and B lymphocytes in AA rats. The articular histopathological changes were also improved.This suggested that Pae had therapeutic effects on AA rats.
2. Effects of SHP-2 inhibitor NSC-87877 on expression of GRK_2 and SHP-2、the level of cAMP、proliferation in synoviocytes from AA rats.
SHP-2 inhibitor NSC-87877 significantly inhibited proliferation of FLS、increased the level of cAMP in synoviocytes and decreased the expression of GRK_2、SHP-2 in FLS.The result of western blot analysis demonstrated that SHP-2 inhibitor NSC-87877(10~（-5）mol·L~(-1)) in vitro significantly decreased the expression of GRK_2 in membrane and increased GRK_2 in cytoplasm.
3. Effects of Pae on expression of GRK_2 and SHP-2、the level of cAMP、proliferation of FLS from AA rats.
Pae significantly inhibited proliferation of FLS、increased the level of cAMP in FLS and decreased the expression of GRK_2、SHP-2.The result of western blot analysis demonstrated that SHP-2 inhibitor NSC-87877(10~（-5）mol·L~(-1)) in vitro significantly decreased the expression of GRK_2 in membrane and increased GRK_2 in cytoplasm.
CONCLUSIONS
1. Pae could alleviate the inflammation of joint at different degree and decrease the spleen index ,the secretion of IL-1,proliferation of T,B lymphocyte and articular histopathological changes in rats with AA.
2. SHP-2 inhibitor could decrease the expression of GRK_2 and SHP-2 in FLS from AA rats; SHP-2 inhibitor inhibited proliferation of FLS by incpreasing the level of cAMP and improving the expresstion of GRK_2 in cytoplasm meanwhile decreased the expression of GRK_2 in membrane.Which indicated that SHP-2 inhibited proliferation of FLS by inhibiting transmembrane of GRK_2 and then increasing the level of cAMP in FLS.
3.Pae could decreased the expression of SHP-2 in FLS,which may be one of the important mechanisms for the Pae on AA rats.
引文
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41.Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-1family and IL-2 receptors. Cytokine Growth Factor Rev. 2003; 14(2): 155-74.
42.Harrington LE, Mangan PR, Weaver CT. Expanding the effector SHP-2 repertoire: the T cell lineage. Curr Opin Immunol.2006; 18(3): 349-56.
43.Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. GRK2: an effector regulatory T cell ties. Immunity. 2006; 24(6): 677-88.
44. Yamauchi, K. et al. Protein-tyrosine-phosphatase SHPTP2 is a required positive effector for insulin downstream signaling. Proc. Natl. Acad. Sci. U. S. A. 2005;92(4) :664-68.
45.McAllister F, Henry A, Kreindler JL, Dubin PJ, Ulrich L, Steele C, Finder JD, Pilewski JM, Carreno BM, Goldman SJ, Pirhonen J, Kolls JK. Role of ERK, ERK, and the ERK receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J Immunol, 2005; 175(1): 404-12.
46.Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y. Vav plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006; 177(1): 566-73.
47.Honorati MC, Neri S, Cattini L, Facchini A. Interleukin-1, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthritis Cartilage.2006; 14(4): 345-52.
48.Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. G protein-coupled receptors activation state charactered by the production of ERK. Biol Chem. 2003; 278(3): 1910-14.
49. Griffiths, E.K. et al. Positive regulation of T cell activation and integrin adhesion by the adapter Fyb Slap. Science.2001;293(2):2260–63.
50.Shahabi S, Hassan ZM, Jazani NH, Ebtekar M. Symphathetic nervous systemplays an important role in the relationship between immune mediated diseases. Med Hypothese. 2006; 67(4): 900-03.
51.Fishman Lobell J, Freidman A, Weiner HL. Different kinetic patterns of cytokine gene expression in vivo in orally tolerant mice. Eur J Immunol. 1994; 24(11): 2720-24.
52. Timms, J.F. et al. SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages. Curr.Biol. 2006;9(6):927-30.
53. Kruger, J. et al. Deficiency of Src homology 2-containing phosphatase 1 results in abnormalities in murine neutrophil function:studies in motheaten mice. J. Immunol. 2000;165(8):5847–9.
54. Saxton, T.The SH2 tyrosine phosphatase Shp2 is required for mammalian limb development. Nat. Genet. 2000;24(3):420-3.
55.Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell. 1996; 85(3): 307-10.
1.Avizienyte E.Src SH3/2 domain-mediated peripheral accumulation of Src and phosphor-myosin is linked to deregulation of E-cadherin and the epitbelial-mesen- cbymal transition.Mol Biol Cell,2004;15(2):2794-803.
2.Yaffe MB.Phosphotyrosine-binding domains in signal transduction.Nat Rev Mol Cell Biol.2002;3(5):177-86.
3.Zou SY.Cantley LC.ZIPcodes for delivering SH-2 domains.Cell.2004; 116(6): 41 -3.
4.Gale NW,Kaplan S,Lowenstein EF.Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras.Nature,2003;363(6):88-92.
5.Young MA,Gonfloni S,Superti FG.Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation.Cell.2007;105(4):115-26.
6.Huang F,Sorkin A.Growth factor receptor binding protein 2-mediated recruitment of the RINC domain of Chl to the epidermal growth factor receptor is essential and sufficient to support receptor endocytosis.Mol Biol Cell.2008;16(3):1268-81.
7.Nagy N,Takahara M,Nishikawa J.Wild-type p53 activates SAP expression in lymphoid cells.Oncogene.2009;23(53):8563-70.
8.Chung AS,Guan YJ,Yuan ZL.Ankyrin repeat and SOCS box 3(ASB3) mediates ubiquitination and degradation of tumor necrosis factor receptor II.Mol Cell Biol.2008;25(11)4716-26.
9.Roche LC,Soenen CV,Grardel DN.Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571.Blood.2007; 100(3):1014-18.
10.Liu WQ,Vidal M,Olszowy C.Structure activity relationships of small phosphopep tides,inhitors of Grb2 SH2 domain.J Med Chem.2009;47(5):223-33.
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12.Brdicka T,Kadlecek TA,Roose JP.Intramoleclar Regulatory Switch in ZAP-70: Analogy with Receptor Tyrosine Kinase.Mol Cell Biol.2005;25(12):4924-33.
13.Tartaglia M,Niemeyer CM,Fraggale A.Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia,myelodysplastic syndromes and acute myeloid leukemia.Nat Gene.2006;34(2):148-50.
14.Kofoed EM,Hwa V,Little B.Growth hormone insensitivity associated with a STAT5b mutation.N Engl J Med.2008;349(12):1139-47.
15.Machida K,Mayer BJ.The SH2 domain:versatile signaling module and pharmaceutical target.Biochim Biophys Acta.2007;1747(1):1-25.
16.Qu CK.The SHP-2 tyrosine phosphatase:signaling mechanisms and biological functions.Cell Res.2000;10(4):279-88.
17.Poole AW,Jones ML.A SHPing tale:perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail. Cell Signal.2005;17(11):1323-32.
18.Neel BG,Gu H,Pao L.The‘SHP’ing news:SH2 domain-containing tyrosine phosphatases in cell signaling.Trends Biochem Sci.2006;28(6):284-93.
18.Du Z,Shen Y,Yang W,et al.Inhibiton of IFN-alpha signaling by a PKC and protein tyrosine phosphatase SHP-2 dependent pathway.Proc Natl Acad Sci USA.2005;102(29):10267-72.
19.Jarvis LA,Toering SJ,Simaon MA.Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases.Development.2006;133(6):11233-42.20.Chan RJ,Johnson SA.A definitive role of SHP-2 tyrosine phosphatase in mediating embryonic stem cell differentiation and hematopoiesis.Blood.2007;102(6):2074-80.
21.Wang FM,Liu HQ,Liu SR.SHP-2promoting migration and metastasis of MCF-7 with loss of E-cadherin,dephosphorylation of FAK and secretion of MMP-9 induced by IL-1 beta in vivo and in vitro.Breast Cancer Res Treat.2005;89(1):5-14.
22.Tsutsumi R,TakahashiA.Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA.Mol Cell Biol.2006;26 (1)261-76.
23.Tartaglia M,Gelb BD.Noonan syndrome and related disorders:genetics and pathogenesis.Annu Rev Genomics Hum Genet.2005;6(7):45-68.
24.Tartaglia M,Martinelli S,Cazzzaniga G.Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.Blood.2004;104(2):307-13.
25.Niihori T,Aoki Y.Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.J Hum Gnent.2005;50(4):192-202.
26.Scapin G,Patel SB,Becker JW.The structural basis for the selectivity of benzotriazole inhibitors of PTP1B.Biochemistry.2008;42(2):11451-59.
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21.Wu H, Wei W, Song LH, Zhang L, ChenY, Hu X. Paeoniflorin induced immune tolerance of mesenteric lymph node lymphocytes via enhancing beta 2-adrenergic receptor desensitization in rats with adjuvant arthritis.Int Immunopharmacol.2007; 7(5): 662-73.
22.Zheng YQ, Wei W, Shen YX, Dai M, Liu LH. Oral and nasal administration of chicken type II collagen suppresses adjuvant arthritis in rats with intestinal lesions induced by meloxicam. World J Gastroenterol.2004; 10(21): 3165-317.
23.Zhang LL, Wei W, Xiao F, Xu JH, Bao CD, Ni LQ, Li XF.“A randomized, double-blind, multi-center, controlled clinical trial of chicken type II collagen in rheumatoid arthritis.”Arthritis Rheum .2008; 59(7): 905-10.
24.Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell. 1996; 85(3): 307-10.
25.Zhang HF,Hou P,Xiao WG. Clinical observation on effect of total glucosides of paeony in treating patients with non-systemic involved Sj?gren syndrome.Zhongguo Zhong Xi Yi Jie He Za Zhi.2007;27(7):596-8.
26.Ming Can Yu, Bao Xue Ge. An essential function for arrestin 2 in the inhibitory signaling of natural killer cells. Nature Immunology.2008; 7(11):1635-42 .
27.Bourdeay A, Dub′e N,Tremblay ML. Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP. Curr. Opin. Cell Biol. 2005;17(4):203-9.
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40.Nagler Anderson C, Bober LA, Robinson ME, Siskind GW, Thorbecke GJ.Suppression of type II collagen-induced arthritis by intragastric administration of soluble type II collagen. Proc Natl Acad Sci USA.1986; 83(19): 7443-46.
41.Moseley TA, Haudenschild DR, Rose L, Reddi AH. Interleukin-1family and IL-2 receptors. Cytokine Growth Factor Rev. 2003; 14(2): 155-74.
42.Harrington LE, Mangan PR, Weaver CT. Expanding the effector SHP-2 repertoire: the T cell lineage. Curr Opin Immunol.2006; 18(3): 349-56.
43.Weaver CT, Harrington LE, Mangan PR, Gavrieli M, Murphy KM. GRK2: an effector regulatory T cell ties. Immunity. 2006; 24(6): 677-88.
44. Yamauchi, K. et al. Protein-tyrosine-phosphatase SHPTP2 is a required positive effector for insulin downstream signaling. Proc. Natl. Acad. Sci. U. S. A. 2005;92(4) :664-68.
45.McAllister F, Henry A, Kreindler JL, Dubin PJ, Ulrich L, Steele C, Finder JD, Pilewski JM, Carreno BM, Goldman SJ, Pirhonen J, Kolls JK. Role of ERK, ERK, and the ERK receptor in regulating growth-related oncogene-alpha and granulocyte colony-stimulating factor in bronchial epithelium: implications for airway inflammation in cystic fibrosis. J Immunol, 2005; 175(1): 404-12.
46.Komiyama Y, Nakae S, Matsuki T, Nambu A, Ishigame H, Kakuta S, Sudo K, Iwakura Y. Vav plays an important role in the development of experimental autoimmune encephalomyelitis. J Immunol. 2006; 177(1): 566-73.
47.Honorati MC, Neri S, Cattini L, Facchini A. Interleukin-1, a regulator of angiogenic factor release by synovial fibroblasts. Osteoarthritis Cartilage.2006; 14(4): 345-52.
48.Aggarwal S, Ghilardi N, Xie MH, de Sauvage FJ, Gurney AL. G protein-coupled receptors activation state charactered by the production of ERK. Biol Chem. 2003; 278(3): 1910-14.
49. Griffiths, E.K. et al. Positive regulation of T cell activation and integrin adhesion by the adapter Fyb Slap. Science.2001;293(2):2260–63.
50.Shahabi S, Hassan ZM, Jazani NH, Ebtekar M. Symphathetic nervous systemplays an important role in the relationship between immune mediated diseases. Med Hypothese. 2006; 67(4): 900-03.
51.Fishman Lobell J, Freidman A, Weiner HL. Different kinetic patterns of cytokine gene expression in vivo in orally tolerant mice. Eur J Immunol. 1994; 24(11): 2720-24.
52. Timms, J.F. et al. SHPS-1 is a scaffold for assembling distinct adhesion-regulated multi-protein complexes in macrophages. Curr.Biol. 2006;9(6):927-30.
53. Kruger, J. et al. Deficiency of Src homology 2-containing phosphatase 1 results in abnormalities in murine neutrophil function:studies in motheaten mice. J. Immunol. 2000;165(8):5847–9.
54. Saxton, T.The SH2 tyrosine phosphatase Shp2 is required for mammalian limb development. Nat. Genet. 2000;24(3):420-3.
55.Feldmann M, Brennan FM, Maini RN. Rheumatoid arthritis. Cell. 1996; 85(3): 307-10.
1.Avizienyte E.Src SH3/2 domain-mediated peripheral accumulation of Src and phosphor-myosin is linked to deregulation of E-cadherin and the epitbelial-mesen- cbymal transition.Mol Biol Cell,2004;15(2):2794-803.
2.Yaffe MB.Phosphotyrosine-binding domains in signal transduction.Nat Rev Mol Cell Biol.2002;3(5):177-86.
3.Zou SY.Cantley LC.ZIPcodes for delivering SH-2 domains.Cell.2004; 116(6): 41 -3.
4.Gale NW,Kaplan S,Lowenstein EF.Grb2 mediates the EGF-dependent activation of guanine nucleotide exchange on Ras.Nature,2003;363(6):88-92.
5.Young MA,Gonfloni S,Superti FG.Dynamic coupling between the SH2 and SH3 domains of c-Src and Hck underlies their inactivation by C-terminal tyrosine phosphorylation.Cell.2007;105(4):115-26.
6.Huang F,Sorkin A.Growth factor receptor binding protein 2-mediated recruitment of the RINC domain of Chl to the epidermal growth factor receptor is essential and sufficient to support receptor endocytosis.Mol Biol Cell.2008;16(3):1268-81.
7.Nagy N,Takahara M,Nishikawa J.Wild-type p53 activates SAP expression in lymphoid cells.Oncogene.2009;23(53):8563-70.
8.Chung AS,Guan YJ,Yuan ZL.Ankyrin repeat and SOCS box 3(ASB3) mediates ubiquitination and degradation of tumor necrosis factor receptor II.Mol Cell Biol.2008;25(11)4716-26.
9.Roche LC,Soenen CV,Grardel DN.Several types of mutations of the Abl gene can be found in chronic myeloid leukemia patients resistant to STI571.Blood.2007; 100(3):1014-18.
10.Liu WQ,Vidal M,Olszowy C.Structure activity relationships of small phosphopep tides,inhitors of Grb2 SH2 domain.J Med Chem.2009;47(5):223-33.
11.Vetrie D,Vorechovsky I,Sideras P.The gene involved in X-linked agammagl- obulinaemia is a member of the src family of protein-tyrosine kinases.Nature. 1993;361(9):226-33.
12.Brdicka T,Kadlecek TA,Roose JP.Intramoleclar Regulatory Switch in ZAP-70: Analogy with Receptor Tyrosine Kinase.Mol Cell Biol.2005;25(12):4924-33.
13.Tartaglia M,Niemeyer CM,Fraggale A.Somatic mutations in PTPN11 in juvenile myelomonocytic leukemia,myelodysplastic syndromes and acute myeloid leukemia.Nat Gene.2006;34(2):148-50.
14.Kofoed EM,Hwa V,Little B.Growth hormone insensitivity associated with a STAT5b mutation.N Engl J Med.2008;349(12):1139-47.
15.Machida K,Mayer BJ.The SH2 domain:versatile signaling module and pharmaceutical target.Biochim Biophys Acta.2007;1747(1):1-25.
16.Qu CK.The SHP-2 tyrosine phosphatase:signaling mechanisms and biological functions.Cell Res.2000;10(4):279-88.
17.Poole AW,Jones ML.A SHPing tale:perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail. Cell Signal.2005;17(11):1323-32.
18.Neel BG,Gu H,Pao L.The‘SHP’ing news:SH2 domain-containing tyrosine phosphatases in cell signaling.Trends Biochem Sci.2006;28(6):284-93.
18.Du Z,Shen Y,Yang W,et al.Inhibiton of IFN-alpha signaling by a PKC and protein tyrosine phosphatase SHP-2 dependent pathway.Proc Natl Acad Sci USA.2005;102(29):10267-72.
19.Jarvis LA,Toering SJ,Simaon MA.Sprouty proteins are in vivo targets of Corkscrew/SHP-2 tyrosine phosphatases.Development.2006;133(6):11233-42.20.Chan RJ,Johnson SA.A definitive role of SHP-2 tyrosine phosphatase in mediating embryonic stem cell differentiation and hematopoiesis.Blood.2007;102(6):2074-80.
21.Wang FM,Liu HQ,Liu SR.SHP-2promoting migration and metastasis of MCF-7 with loss of E-cadherin,dephosphorylation of FAK and secretion of MMP-9 induced by IL-1 beta in vivo and in vitro.Breast Cancer Res Treat.2005;89(1):5-14.
22.Tsutsumi R,TakahashiA.Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA.Mol Cell Biol.2006;26 (1)261-76.
23.Tartaglia M,Gelb BD.Noonan syndrome and related disorders:genetics and pathogenesis.Annu Rev Genomics Hum Genet.2005;6(7):45-68.
24.Tartaglia M,Martinelli S,Cazzzaniga G.Genetic evidence for lineage-related and differentiation stage-related contribution of somatic PTPN11 mutations to leukemogenesis in childhood acute leukemia.Blood.2004;104(2):307-13.
25.Niihori T,Aoki Y.Functional analysis of PTPN11/SHP-2 mutants identified in Noonan syndrome and childhood leukemia.J Hum Gnent.2005;50(4):192-202.
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