非视紫质G蛋白偶联受体激酶对肿瘤的调控作用
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摘要
G蛋白偶联受体激酶(G protein-coupled receptor kinases, GRKs)通过特异性地磷酸化活化状态的G蛋白偶联受体(G protein-coupled receptors, GPCRs)终止GPCR信号转导、以及磷酸化非GPCR等参与广泛细胞生理和病理活动。近些年有关GRKs与肿瘤发生和演进的关系研究取得了长足进展,但详细的分子机制有待进一步揭示。本文讨论非视紫质GRKs对多种肿瘤细胞的不同调控作用,以期为深入开展该领域研究提供新思路。
G protein-coupled receptor kinases(GRKs) are involved in a wide range of cellular physiology and pathological activities by specifically phosphorylating activated G-protein coupled receptors(GPCRs)to terminate GPCR signaling and phosphorylating non-GPCR substrates. Although significant progress has been made in the study of the relationship between GRKs and tumor pathogenesis in recent years, the detailed molecular mechanism needs to be further elucidated. This article discusses the diverse role of non-rhodopsin GRKs in the regulation of a variety of tumor cells, with the goal to provide new ideas for further research in this field.
G protein-coupled receptor kinases(GRKs) are involved in a wide range of cellular physiology and pathological activities by specifically phosphorylating activated G-protein coupled receptors(GPCRs)to terminate GPCR signaling and phosphorylating non-GPCR substrates. Although significant progress has been made in the study of the relationship between GRKs and tumor pathogenesis in recent years, the detailed molecular mechanism needs to be further elucidated. This article discusses the diverse role of non-rhodopsin GRKs in the regulation of a variety of tumor cells, with the goal to provide new ideas for further research in this field.
引文
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[2]Willets JM,Challiss RA,Nahorski SR.Non-visual GRKs:are we seeing the whole picture[J].Trends Pharmacol Sci,2003,24(12):626-33.
[3]Komolov KE,Benovic JL.G protein-coupled receptor kinases:Past,present and future[J].Cell Signal,2018,41:17-24.
[4]Jiang X,Benovic JL,Wedegaertner PB.Plasma membrane and nuclear localization of G protein coupled receptor kinase 6A[J].Mol Biol Cell,2007,18(8):2960-9.
[5]Homan KT,Tesmer JJ.Structural insights into G protein-coupled receptor kinase function[J].Curr Opin Cell Biol,2014,27:25-31.
[6]Pitcher JA,Fredericks ZL,Stone WC,et al.Phosphatidylinositol4,5-bisphosphate(PIP2)-enhanced G protein-coupled receptor kinase(GRK)activity.Location,structure,and regulation of the PIP2 binding site distinguishes the GRK subfamilies[J].J Biol Chem,1996,271(40):24907-13.
[7]Thiyagarajan MM,Stracquatanio RP,Pronin AN,et al.A predicted amphipathic helix mediates plasma membrane localization of GRK5[J].J Biol Chem,2004,279(17):17989-95.
[8]Martini JS,Raake P,Vinge LE,et al.Uncovering G proteincoupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes[J].Proc Natl Acad Sci USA,2008,105(34):12457-62.
[9]Usui I,Imamura T,Babendure JL,et al.G protein-coupled receptor kinase 2 mediates endothelin-1-induced insulin resistance via the inhibition of both Galphaq/11 and insulin receptor substrate-1pathways in 3T3-L1 adipocytes[J].Mol Endocrinol,2005,19(11):2760-8.
[10]Sorriento D,Ciccarelli M,Santulli G,et al.The G-protein-coupled receptor kinase 5 inhibits NFkappaB transcriptional activity by inducing nuclear accumulation of IkappaB alpha[J].Proc Natl Acad Sci U S A,2008,105(46):17818-23.
[11]Chen X,Zhu H,Yuan M,et al.G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis[J].J Biol Chem,2010,285(17):12823-30.
[12]Michal AM,So CH,Beeharry N,et al.G Protein-coupled receptor kinase 5 is localized to centrosomes and regulates cell cycle progression[J].J Biol Chem,2012,287(9):6928-40.
[13]Nakaya M,Tajima M,Kosako H,et al.GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance[J].Nat Commun,2013,4:1532.
[14]Perroy J,Adam L,Qanbar R,et al.Phosphorylation-independent desensitization of GABA(B)receptor by GRK4[J].EMBO J,2003,22(15):3816-24.
[15]Penela P,Ribas C,Aymerich I,et al.New roles of G proteincoupled receptor kinase 2(GRK2)in cell migration[J].Cell Adh Migr,2009,3(1):19-23.
[16]Yuan L,Zhang H,Rubin JB,et al.Growth factor receptor-Srcmediated suppression of GRK6 dysregulates CXCR4 signaling and promotes medulloblastoma migration[J].Mol Cancer,2013,12:18.
[17]Villar VA,Jones JE,Armando I,et al.G protein-coupled receptor kinase 4(GRK4)regulates the phosphorylation and function of the dopamine D3 receptor[J].J Biol Chem,2009,284(32):21425-34.
[18]So CH,Michal AM,Mashayekhi R,et al.G protein-coupled receptor kinase 5 phosphorylates nucleophosmin and regulates cell sensitivity to polo-like kinase 1 inhibition[J].J Biol Chem,2012,287(21):17088-99.
[19]Johnson LR,Robinson JD,Lester KN,et al.Distinct structural features of G protein-coupled receptor kinase 5(GRK5)regulate its nuclear localization and DNA-binding ability[J].PloS One,2013,8(5):e62508.
[20]Gold JI,Martini JS,Hullmann J,et al.Nuclear translocation of cardiac G protein-Coupled Receptor kinase 5 downstream of select Gq-activating hypertrophic ligands is a calmodulindependent process[J].PLoS One,2013,8(3):e57324.
[21]So CH,Michal A,Komolov KE,et al.G protein-coupled receptor kinase 2(GRK2)is localized to centrosomes and mediates epidermal growth factor-promoted centrosomal separation[J].Mol Biol Cell,2013,24(18):2795-806.
[22]Michal AM,So CH,Beeharry N,et al.G protein-coupled receptor kinase 5 is localized to centrosomes and regulates cell cycle progression[J].J Biol Chem,2012,287(9):6928-40.
[23]Xiao P,Huang X,Huang L,et al.G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling[J].Exp Cell Res,2017,360(2):273-80.
[24]Cerami E,Gao J,Dogrusoz U,et al.The cBio cancer genomics portal:an open platform for exploring multidimensional cancer genomics data[J].Cancer Discovery,2012,2(5):401-4.
[25]Gao J,Aksoy BA,Dogrusoz U,et al.Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal[J].Sci Signal,2013,6(269):pl1.
[26]Ribas C,Penela P,Murga C,et al.The G protein-coupled receptor kinase(GRK)interactome:Role of GRKs in GPCR regulation and signaling[J].Biochim Biophys Acta,2007,1768(4):913-22.
[27]MétayéT,Levillain P,Kraimps JL,et al.Immunohistochemical detection,regulation and antiproliferative function of G-proteincoupled receptor kinase 2 in thyroid carcinomas[J].J Endocrinol,2008,198(1):101-10.
[28]Lin SB,Zhou L,Liang ZY,et al.Expression of GRK2 and IGF1Rin hepatocellular carcinoma:clinicopathological and prognostic significance[J].J Clin Pathol,2017,70(9):754-9.
[29]Zhou L,Wang MY,Liang ZY,et al.G-protein-coupled receptor kinase 2 in pancreatic cancer:clinicopathologic and prognostic significance[J].Hum Pathol,2016,56:171-7.
[30]Nogués L,Reglero C,Rivas V,et al.G protein-coupled receptor kinase 2(GRK2)promotes breast tumorigenesis through a HDAC6-Pin1 axis[J].Ebiomedicine,2016,13:132-45.
[31]Zhang F,Xiang S,Cao Y,et al.EIF3D promotes gallbladder cancer development by stabilizing GRK2 kinase and activating PI3K-AKT signaling pathway[J].Cell Death Dis,2017,8(6):e2868.
[32]Crassini K,Pyke T,Shen Y,et al.Inhibition of the Raf-1 kinase inhibitory protein(RKIP)by locostatin induces cell death and reduces the CXCR4-mediated migration of chronic lymphocytic leukemia cells[J].Leuk Lymphoma,2018,59(12):2917-28.
[33]Billard MJ,Fitzhugh DJ,Parker JS,et al.G protein coupled receptor kinase 3 regulates breast cancer migration,invasion,and metastasis[J].PloS One,2016,11(4):e0152856.
[34]Sang M,Hulsurkar M,Zhang X,et al.GRK3 is a direct target of CREB activation and regulates neuroendocrine differentiation of prostate cancer cells[J].Oncotarget,2016,7(29):45171-85.
[35]Jiang T,Yang C,Ma L,et al.Overexpression of GRK3,Promoting Tumor Proliferation,Is Predictive of Poor Prognosis in Colon Cancer[J].Dis Markers,2017,2017:1202710.
[36]Jin Y,Liang ZY,Zhou WX,et al.Expression and Significances of G-Protein-Coupled Receptor Kinase 3 in Hepatocellular Carcinoma[J].J Cancer,2017,8(11):1972-8.
[37]Woerner BM,Luo J,Brown KR,et al.Suppression of G-proteincoupled receptor kinase 3 expression is a feature of classical GBMthat is required for maximal growth[J].Mol Cancer Res,2012,10(1):156-66.
[38]Matsubayashi J,Takanashi M,Oikawa K,et al.Expression of Gprotein-coupled receptor kinase 4 is associated with breast cancer tumourigenesis[J].J Pathol,2010,216(3):317-27.
[39]Voigt C,Holzapfel HP,Meyer S,et al.Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules[J].J Endocrinol,2004,182(1):173-82.
[40]King DW,Steinmetz R,Wagoner HA,et al.Differential expression of GRK isoforms in nonmalignant and malignant human granulosacells[J].Endocrine,2003,22(2):135-41.
[41]Kim JI,Chakraborty P,Wang Z,et al.G-protein coupled receptor kinase 5 regulates prostate tumor growth[J].J Urol,2012,187(1):322-9.
[42]Gambardella J,Franco A,Giudice CD,et al.Dual role of GRK5in cancer development and progression[J].Transl Med UniSa,2016,14:28-37.
[43]Jiang LP,Fan SQ,Xiong QX,et al.GRK5 functions as an oncogenic factor in non-small-cell lung cancer[J].Cell Death&Dis,2018,9(3):295.
[44]Yao S,Zhong L,Liu J,et al.Prognostic value of decreased GRK6expression in lung adenocarcinoma[J].J Cancer Res Clin Oncol,2016,142(12):25411-9.
[45]Xu LQ,Tan SB,Huang S,et al.G protein-coupled receptor kinase 6 is overexpressed in glioma and promotes glioma cell proliferation[J].Oncotarget,2017,8(33):54227-35.
[46]Ozawa PMM,Ariza CB,Ishibashi CM,etal.Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma[J].Int J Cancer,2015,138(1):10-3.
[47]Che X,Zhang G,Zhang X,et al.Overexpression of G proteincoupled receptor kinase 6(GRK6)is associated with progression and poor prognosis of papillary thyroid carcinoma[J].Med Sci Monit,2018,24:3540-8.
[48]Tao R,Li Q,Gao X,et al.Overexpression of GRK6 associates with the progression and prognosis of colorectal carcinoma[J].Oncol Lett,2018,15(4):5879-86.
[49]Yin Y,Xu X,Tang J,et al.CD97 promotes tumor aggressiveness through the traditional G protein-coupled receptor-mediated signaling in hepatocellular carcinoma[J].Hepatology,2018,68(5):1865-78.
[50]Qiu X,Chen J,Zhang Z,et al.Aberrant GRK6 promoter ethylation is associated with poor prognosis in hypopharyngeal squamous cell carcinoma[J].Oncol Rep,2016,35(2):1027-33.
[2]Willets JM,Challiss RA,Nahorski SR.Non-visual GRKs:are we seeing the whole picture[J].Trends Pharmacol Sci,2003,24(12):626-33.
[3]Komolov KE,Benovic JL.G protein-coupled receptor kinases:Past,present and future[J].Cell Signal,2018,41:17-24.
[4]Jiang X,Benovic JL,Wedegaertner PB.Plasma membrane and nuclear localization of G protein coupled receptor kinase 6A[J].Mol Biol Cell,2007,18(8):2960-9.
[5]Homan KT,Tesmer JJ.Structural insights into G protein-coupled receptor kinase function[J].Curr Opin Cell Biol,2014,27:25-31.
[6]Pitcher JA,Fredericks ZL,Stone WC,et al.Phosphatidylinositol4,5-bisphosphate(PIP2)-enhanced G protein-coupled receptor kinase(GRK)activity.Location,structure,and regulation of the PIP2 binding site distinguishes the GRK subfamilies[J].J Biol Chem,1996,271(40):24907-13.
[7]Thiyagarajan MM,Stracquatanio RP,Pronin AN,et al.A predicted amphipathic helix mediates plasma membrane localization of GRK5[J].J Biol Chem,2004,279(17):17989-95.
[8]Martini JS,Raake P,Vinge LE,et al.Uncovering G proteincoupled receptor kinase-5 as a histone deacetylase kinase in the nucleus of cardiomyocytes[J].Proc Natl Acad Sci USA,2008,105(34):12457-62.
[9]Usui I,Imamura T,Babendure JL,et al.G protein-coupled receptor kinase 2 mediates endothelin-1-induced insulin resistance via the inhibition of both Galphaq/11 and insulin receptor substrate-1pathways in 3T3-L1 adipocytes[J].Mol Endocrinol,2005,19(11):2760-8.
[10]Sorriento D,Ciccarelli M,Santulli G,et al.The G-protein-coupled receptor kinase 5 inhibits NFkappaB transcriptional activity by inducing nuclear accumulation of IkappaB alpha[J].Proc Natl Acad Sci U S A,2008,105(46):17818-23.
[11]Chen X,Zhu H,Yuan M,et al.G-protein-coupled receptor kinase 5 phosphorylates p53 and inhibits DNA damage-induced apoptosis[J].J Biol Chem,2010,285(17):12823-30.
[12]Michal AM,So CH,Beeharry N,et al.G Protein-coupled receptor kinase 5 is localized to centrosomes and regulates cell cycle progression[J].J Biol Chem,2012,287(9):6928-40.
[13]Nakaya M,Tajima M,Kosako H,et al.GRK6 deficiency in mice causes autoimmune disease due to impaired apoptotic cell clearance[J].Nat Commun,2013,4:1532.
[14]Perroy J,Adam L,Qanbar R,et al.Phosphorylation-independent desensitization of GABA(B)receptor by GRK4[J].EMBO J,2003,22(15):3816-24.
[15]Penela P,Ribas C,Aymerich I,et al.New roles of G proteincoupled receptor kinase 2(GRK2)in cell migration[J].Cell Adh Migr,2009,3(1):19-23.
[16]Yuan L,Zhang H,Rubin JB,et al.Growth factor receptor-Srcmediated suppression of GRK6 dysregulates CXCR4 signaling and promotes medulloblastoma migration[J].Mol Cancer,2013,12:18.
[17]Villar VA,Jones JE,Armando I,et al.G protein-coupled receptor kinase 4(GRK4)regulates the phosphorylation and function of the dopamine D3 receptor[J].J Biol Chem,2009,284(32):21425-34.
[18]So CH,Michal AM,Mashayekhi R,et al.G protein-coupled receptor kinase 5 phosphorylates nucleophosmin and regulates cell sensitivity to polo-like kinase 1 inhibition[J].J Biol Chem,2012,287(21):17088-99.
[19]Johnson LR,Robinson JD,Lester KN,et al.Distinct structural features of G protein-coupled receptor kinase 5(GRK5)regulate its nuclear localization and DNA-binding ability[J].PloS One,2013,8(5):e62508.
[20]Gold JI,Martini JS,Hullmann J,et al.Nuclear translocation of cardiac G protein-Coupled Receptor kinase 5 downstream of select Gq-activating hypertrophic ligands is a calmodulindependent process[J].PLoS One,2013,8(3):e57324.
[21]So CH,Michal A,Komolov KE,et al.G protein-coupled receptor kinase 2(GRK2)is localized to centrosomes and mediates epidermal growth factor-promoted centrosomal separation[J].Mol Biol Cell,2013,24(18):2795-806.
[22]Michal AM,So CH,Beeharry N,et al.G protein-coupled receptor kinase 5 is localized to centrosomes and regulates cell cycle progression[J].J Biol Chem,2012,287(9):6928-40.
[23]Xiao P,Huang X,Huang L,et al.G protein-coupled receptor kinase 4-induced cellular senescence and its senescence-associated gene expression profiling[J].Exp Cell Res,2017,360(2):273-80.
[24]Cerami E,Gao J,Dogrusoz U,et al.The cBio cancer genomics portal:an open platform for exploring multidimensional cancer genomics data[J].Cancer Discovery,2012,2(5):401-4.
[25]Gao J,Aksoy BA,Dogrusoz U,et al.Integrative Analysis of Complex Cancer Genomics and Clinical Profiles Using the cBioPortal[J].Sci Signal,2013,6(269):pl1.
[26]Ribas C,Penela P,Murga C,et al.The G protein-coupled receptor kinase(GRK)interactome:Role of GRKs in GPCR regulation and signaling[J].Biochim Biophys Acta,2007,1768(4):913-22.
[27]MétayéT,Levillain P,Kraimps JL,et al.Immunohistochemical detection,regulation and antiproliferative function of G-proteincoupled receptor kinase 2 in thyroid carcinomas[J].J Endocrinol,2008,198(1):101-10.
[28]Lin SB,Zhou L,Liang ZY,et al.Expression of GRK2 and IGF1Rin hepatocellular carcinoma:clinicopathological and prognostic significance[J].J Clin Pathol,2017,70(9):754-9.
[29]Zhou L,Wang MY,Liang ZY,et al.G-protein-coupled receptor kinase 2 in pancreatic cancer:clinicopathologic and prognostic significance[J].Hum Pathol,2016,56:171-7.
[30]Nogués L,Reglero C,Rivas V,et al.G protein-coupled receptor kinase 2(GRK2)promotes breast tumorigenesis through a HDAC6-Pin1 axis[J].Ebiomedicine,2016,13:132-45.
[31]Zhang F,Xiang S,Cao Y,et al.EIF3D promotes gallbladder cancer development by stabilizing GRK2 kinase and activating PI3K-AKT signaling pathway[J].Cell Death Dis,2017,8(6):e2868.
[32]Crassini K,Pyke T,Shen Y,et al.Inhibition of the Raf-1 kinase inhibitory protein(RKIP)by locostatin induces cell death and reduces the CXCR4-mediated migration of chronic lymphocytic leukemia cells[J].Leuk Lymphoma,2018,59(12):2917-28.
[33]Billard MJ,Fitzhugh DJ,Parker JS,et al.G protein coupled receptor kinase 3 regulates breast cancer migration,invasion,and metastasis[J].PloS One,2016,11(4):e0152856.
[34]Sang M,Hulsurkar M,Zhang X,et al.GRK3 is a direct target of CREB activation and regulates neuroendocrine differentiation of prostate cancer cells[J].Oncotarget,2016,7(29):45171-85.
[35]Jiang T,Yang C,Ma L,et al.Overexpression of GRK3,Promoting Tumor Proliferation,Is Predictive of Poor Prognosis in Colon Cancer[J].Dis Markers,2017,2017:1202710.
[36]Jin Y,Liang ZY,Zhou WX,et al.Expression and Significances of G-Protein-Coupled Receptor Kinase 3 in Hepatocellular Carcinoma[J].J Cancer,2017,8(11):1972-8.
[37]Woerner BM,Luo J,Brown KR,et al.Suppression of G-proteincoupled receptor kinase 3 expression is a feature of classical GBMthat is required for maximal growth[J].Mol Cancer Res,2012,10(1):156-66.
[38]Matsubayashi J,Takanashi M,Oikawa K,et al.Expression of Gprotein-coupled receptor kinase 4 is associated with breast cancer tumourigenesis[J].J Pathol,2010,216(3):317-27.
[39]Voigt C,Holzapfel HP,Meyer S,et al.Increased expression of G-protein-coupled receptor kinases 3 and 4 in hyperfunctioning thyroid nodules[J].J Endocrinol,2004,182(1):173-82.
[40]King DW,Steinmetz R,Wagoner HA,et al.Differential expression of GRK isoforms in nonmalignant and malignant human granulosacells[J].Endocrine,2003,22(2):135-41.
[41]Kim JI,Chakraborty P,Wang Z,et al.G-protein coupled receptor kinase 5 regulates prostate tumor growth[J].J Urol,2012,187(1):322-9.
[42]Gambardella J,Franco A,Giudice CD,et al.Dual role of GRK5in cancer development and progression[J].Transl Med UniSa,2016,14:28-37.
[43]Jiang LP,Fan SQ,Xiong QX,et al.GRK5 functions as an oncogenic factor in non-small-cell lung cancer[J].Cell Death&Dis,2018,9(3):295.
[44]Yao S,Zhong L,Liu J,et al.Prognostic value of decreased GRK6expression in lung adenocarcinoma[J].J Cancer Res Clin Oncol,2016,142(12):25411-9.
[45]Xu LQ,Tan SB,Huang S,et al.G protein-coupled receptor kinase 6 is overexpressed in glioma and promotes glioma cell proliferation[J].Oncotarget,2017,8(33):54227-35.
[46]Ozawa PMM,Ariza CB,Ishibashi CM,etal.Role of CXCL12 and CXCR4 in normal cerebellar development and medulloblastoma[J].Int J Cancer,2015,138(1):10-3.
[47]Che X,Zhang G,Zhang X,et al.Overexpression of G proteincoupled receptor kinase 6(GRK6)is associated with progression and poor prognosis of papillary thyroid carcinoma[J].Med Sci Monit,2018,24:3540-8.
[48]Tao R,Li Q,Gao X,et al.Overexpression of GRK6 associates with the progression and prognosis of colorectal carcinoma[J].Oncol Lett,2018,15(4):5879-86.
[49]Yin Y,Xu X,Tang J,et al.CD97 promotes tumor aggressiveness through the traditional G protein-coupled receptor-mediated signaling in hepatocellular carcinoma[J].Hepatology,2018,68(5):1865-78.
[50]Qiu X,Chen J,Zhang Z,et al.Aberrant GRK6 promoter ethylation is associated with poor prognosis in hypopharyngeal squamous cell carcinoma[J].Oncol Rep,2016,35(2):1027-33.