膜联蛋白A2磷酸化与功能调控研究进展
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摘要
膜联蛋白A2(AnxA2)是一种多功能蛋白,通过多种翻译后修饰来调控其复杂的功能。蛋白质磷酸化是目前最受关注的AnxA2翻译后修饰方式,Ser11、Ser25和Tyr23是最主要的3个磷酸化位点。磷酸化对AnxA2功能调控的可能影响一直是热门话题。近年来研究发现在肿瘤细胞外泌体中也存在AnxA2表达,故对AnxA2及其磷酸化的研究也从细胞内拓展至细胞外。AnxA2及其磷酸化的研究在众多临床学科领域也取得了令人瞩目的成果。本文就Ser11、Ser25和Tyr23磷酸化位点对AnxA2功能调控的影响及其在外泌体中的研究进展作一综述。
Annexin A2(AnxA2) is a multifunctional protein and has complex functions regulated by post-translational modi?cations. Protein phosphorylation is the most popular post-translational modi?cation of AnxA2. Ser11, Ser25 and Tyr23 are the three most important phosphorylation sites. The possible impact of phosphorylation of AnxA2 function regulation has always been a hot topic. Recently, AnxA2 has been found in the exosomes of tumor cells, and the research of AnxA2 and its phosphorylation has been expanded from intracellular to extracellular. Remarkable achievements in the study of AnxA2 and its phosphorylation have been made in many clinical disciplines. This paper reviewed the advances on the impact of phosphorylation of Ser11, Ser25, Tyr23 sites on AnxA2 function regulation and the research about AnxA2 in exosomes.
Annexin A2(AnxA2) is a multifunctional protein and has complex functions regulated by post-translational modi?cations. Protein phosphorylation is the most popular post-translational modi?cation of AnxA2. Ser11, Ser25 and Tyr23 are the three most important phosphorylation sites. The possible impact of phosphorylation of AnxA2 function regulation has always been a hot topic. Recently, AnxA2 has been found in the exosomes of tumor cells, and the research of AnxA2 and its phosphorylation has been expanded from intracellular to extracellular. Remarkable achievements in the study of AnxA2 and its phosphorylation have been made in many clinical disciplines. This paper reviewed the advances on the impact of phosphorylation of Ser11, Ser25, Tyr23 sites on AnxA2 function regulation and the research about AnxA2 in exosomes.
引文
[1]SCHLOER S,PAJONCZYK D,RESCHER U.Annexins in translational research:hidden treasures to be found[J/OL].Int J Mol Sci,2018,19.pii:E1781.doi:10.3390/ijms19061781.
[2]GRINDHEIM A K,SARASTE J,VEDELER A.Protein phosphorylation and its role in the regulation of Annexin A2 function[J].Biochim Biophys Acta Gen Subj,2017,1861(11 Pt A):2515-2529.
[3]TEIJEIRO J M,ROLDáN M L,MARINI P E.Annexin A2 and S100A10 in the mammalian oviduct[J].Cell Tissue Res,2016,363:567-577.
[4]YANG W,MEI F C,CHENG X.EPAC1 regulates endothelial annexin A2 cell surface translocation and plasminogen activation[J].FASEB J,2018,32:2212-2222.
[5]TAYLOR J R,FERNANDEZ D J,THORNTON SM,SKEATE J G,LüHEN K P,DA SILVA D M,et al.Heterotetrameric annexin A2/S100A10(A2t)is essential for oncogenic human papillomavirus trafficking and capsid disassembly,and protects virions from lysosomal degradation[J/OL].Sci Rep,2018,8:11642.doi:10.1038/s41598-018-30051-2.
[6]KUMAR A,KUHN L T,BALBACH J.In-cell NMR:analysis of protein-small molecule interactions,metabolic processes,and protein phosphorylation[J/OL].Int J Mol Sci,2019,20.pii:E378.doi:10.3390/ijms20020378.
[7]LOU Y,YU Y,XU X,ZHOU S,SHEN H,FAN T,et al.Long non-coding RNA LUCAT1 promotes tumourigenesis by inhibiting ANXA2 phosphorylation in hepatocellular carcinoma[J].J Cell Mol Med,2019,23:1873-1884.
[8]CHEN C Y,LIN Y S,CHEN C H,CHEN Y J.Annexin A2-mediated cancer progression and therapeutic resistance in nasopharyngeal carcinoma[J/OL].J Biomed Sci,2018,25:30.doi:10.1186/s12929-018-0430-8.
[9]YUAN J,YANG Y,GAO Z,WANG Z,JI W,SONG W,et al.Tyr23 phosphorylation of AnxA2 enhances STAT3activation and promotes proliferation and invasion of breast cancer cells[J].Breast Cancer Res Treat,2017,164:327-340.
[10]BORTHWICK L A,NEAL A,HOBSON L,GERKEV,ROBSON L,MUIMO R.The annexin 2-S100A10complex and its association with TRPV6 is regulated by cAMP/PKA/CnA in airway and gut epithelia[J].Cell Calcium,2008,44:147-157.
[11]GABEL M,CHASSEROT-GOLAZ S.Annexin A2,an essential partner of the exocytotic process in chromaffin cells[J].J Neurochem,2016,137:890-896.
[12]CHASSEROT-GOLAZ S,VITALE N,UMBRECHT-JENCK E,KNIGHT D,GERKE V,BADER M F.Annexin 2 promotes the formation of lipid microdomains required for calcium-regulated exocytosis of dense-core vesicles[J].Mol Biol Cell,2005,16:1108-1119.
[13]AYALA-SANMARTIN J,GOUACHE P,HENRY J P.N-terminal domain of annexin 2 regulates Ca2+-dependent membrane aggregation by the core domain:a site directed mutagenesis study[J].Biochemistry,2000,39:15190-15198.
[14]BRANDHERM I,DISSE J,ZEUSCHNER D,GERKEV.cAMP-induced secretion of endothelial von Willebrand factor is regulated by a phosphorylation/dephosphorylation switch in annexin A2[J].Blood,2013,122:1042-1051.
[15]HOLTHENRICH A,GERKE V.Regulation of vonWillebrand factor secretion from endothelial cells by the annexin A2-S100A10 complex[J/OL].Int J Mol Sci,2018,19.pii:E1752.doi:10.3390/ijms19061752.
[16]HEDHLI N,FALCONE D J,HUANG B,CESARMAN-MAUS G,KRAEMER R,ZHAI H,et al.The annexin A2/S100A10 system in health and disease:emerging paradigms[J/OL].J Biomed Biotechnol,2012,2012:406273.doi:10.1155/2012/406273.
[17]BORTHWICK L A,MCGAW J,CONNER G,TAYLORC J,GERKE V,MEHTA A,et al.The formation of the cAMP/protein kinase A-dependent annexin 2-S100A10complex with cystic fibrosis conductance regulator protein(CFTR)regulates CFTR channel function[J].Mol Biol Cell,2007,18:3388-3397.
[18]AUKRUST I,HOLL?S H,STRAND E,EVENSEN L,TRAVéG,FLATMARK T,et al.The mRNA-binding site of annexin A2 resides in helices C-D of its domainⅣ[J].J Mol Biol,2007,368:1367-1378.
[19]VEDELER A,HOLL?S H,GRINDHEIM A K,RADDUM A M.Multiple roles of annexin A2 in posttranscriptional regulation of gene expression[J].Curr Protein Pept Sci,2012,13:401-412.
[20]AUKRUST I,ROSENBERG L A,ANKERUD M M,BERTELSEN V,HOLL?S H,SARASTE J,et al.Posttranslational modifications of Annexin A2 are linked to its association with perinuclear nonpolysomal mRNPcomplexes[J].FEBS Open Bio,2017,7:160-173.
[21]GRINDHEIM A K,HOLL?S H,RAMIREZ J,SARASTE J,TRAVéG,VEDELER A.Effect of serine phosphorylation and Ser25 phospho-mimicking mutations on nuclear localisation and ligand interactions of annexin A2[J].J Mol Biol,2014,426:2486-2499.
[22]CARON D,BOUTCHUENG-DJIDJOU M,TANGUAYR M,FAURE R L.Annexin A2 is SUMOylated on its N-terminal domain:regulation by insulin[J].FEBS Lett,2015,589:985-991.
[23]HAYES M J,SHAO D,BAILLY M,MOSS S E.Regulation of actin dynamics by annexin 2[J].EMBO J,2006,25:1816-1826.
[24]RESCHER U,LUDWIG C,KONIETZKO V,KHARITONENKOV A,GERKE V.Tyrosine phosphorylation of annexin A2 regulates Rho-mediated actin rearrangement and cell adhesion[J].J Cell Sci,2008,121(Pt 13):2177-2185.
[25]DE GRAAUW M,TIJDENS I,SMEETS M B,HENSBERGEN P J,DEELDER A M,VAN DE WATERB.Annexin A2 phosphorylation mediates cell scattering and branching morphogenesis via cofilin activation[J].Mol Cell Biol,2008,28:1029-1040.
[26]CUI H Y,WANG S J,MIAO J Y,FU Z G,FENG F,WUJ,et al.CD147 regulates cancer migration via direct interaction with Annexin A2 and DOCK3-β-cateninWAVE2 signaling[J].Oncotarget,2016,7:5613-5629.
[27]HAYES M J,MOSS S E.Annexin 2 has a dual role as regulator and effector of v-Src in cell transformation[J].JBiol Chem,2009,284:10202-10210.
[28]GABEL M,DELAVOIE F,ROYER C,TAHOULYT,GASMAN S,BADER M F,et al.Phosphorylation cycling of Annexin A2 Tyr23 is critical for calciumregulated exocytosis in neuroendocrine cells[J/OL].Biochim Biophys Acta Mol Cell Res,2019.pii:S0167-4889(18)30542-1.doi:10.1016/j.bbamcr.2018.12.013.
[29]TAURO B J,MATHIAS R A,GREENING D W,GOPALS K,JI H,KAPP E A,et al.Oncogenic H-ras reprograms Madin-Darby canine kidney(MDCK)cell-derived exosomal proteins following epithelial-mesenchymal transition[J].Mol Cell Proteomics,2013,12:2148-2159.
[30]BRONISZ A,WANG Y,NOWICKI M O,PERUZZIP,ANSARI K,OGAWA D,et al.Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1[J].Cancer Res,2014,74:738-750.
[31]PRASAD S,GUPTA S C,TYAGI A K.Reactive oxygen species(ROS)and cancer:role of antioxidative nutraceuticals[J].Cancer Lett,2017,387:95-105.
[32]ZOU Z,CHANG H,LI H,WANG S.Induction of reactive oxygen species:an emerging approach for cancer therapy[J].Apoptosis,2017,22:1321-1335..
[33]GRINDHEIM A K,HOLL?S H,RADDUM A M,SARASTE J,VEDELER A.Reactive oxygen species exert opposite effects on Tyr23 phosphorylation of the nuclear and cortical pools of annexin A2[J].J Cell Sci,2016,129:314-328.
[34]GRINDHEIM A K,VEDELER A.Extracellular vesicles released from cells exposed to reactive oxygen species increase annexin A2 expression and survival of target cells exposed to the same conditions[J/OL].Commun Integr Biol,2016,9:e1191715.doi:10.1080/19420889.2016.1191715.
[35]MOHAMMAD H S,KUROKOHCHI K,YONEYAMAH,TOKUDA M,MORISHITA A,JIAN G,et al.Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma[J].Int J Oncol,2008,33:1157-1163.
[36]CHAUDHARY P,THAMAKE S I,SHETTY P,VISHWANATHA J K.Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies[J].Br J Cancer,2014,111:2328-2341.
[37]DATHE C,DAIGELER A L,SEIFERT W,JANKOWSKIV,MROWKA R,KALIS R,et al.Annexin A2 mediates apical trafficking of renal Na+-K+-2Cl-cotransporter[J].J Biol Chem,2014,289:9983-9997.
[38]DIAZ B,ELKBULI A,EHRHARDT J D Jr,MCKENNEY M,BONEVA D,HAI S.Pheochromocytoma-related cardiomyopathy presenting as broken heart syndrome:case report and literature review[J].Int J Surg Case Rep,2019,55:7-10.
[39]RADDUM A M,EVENSEN L,HOLL?S H,GRINDHEIMA K,LORENS J B,VEDELER A.DomainsⅠandⅣof annexin A2 affect the formation and integrity of in vitro capillary-like networks[J/OL].PLoS One,2013,8:e60281.doi:10.1371/journal.pone.0060281.
[40]LIMA E SILVA R,SHEN J,GONG Y Y,SEIDEL C P,HACKETT S F,KESAVAN K,et al.Agents that bind annexin A2 suppress ocular neovascularization[J].J Cell Physiol,2010,225:855-864.
[2]GRINDHEIM A K,SARASTE J,VEDELER A.Protein phosphorylation and its role in the regulation of Annexin A2 function[J].Biochim Biophys Acta Gen Subj,2017,1861(11 Pt A):2515-2529.
[3]TEIJEIRO J M,ROLDáN M L,MARINI P E.Annexin A2 and S100A10 in the mammalian oviduct[J].Cell Tissue Res,2016,363:567-577.
[4]YANG W,MEI F C,CHENG X.EPAC1 regulates endothelial annexin A2 cell surface translocation and plasminogen activation[J].FASEB J,2018,32:2212-2222.
[5]TAYLOR J R,FERNANDEZ D J,THORNTON SM,SKEATE J G,LüHEN K P,DA SILVA D M,et al.Heterotetrameric annexin A2/S100A10(A2t)is essential for oncogenic human papillomavirus trafficking and capsid disassembly,and protects virions from lysosomal degradation[J/OL].Sci Rep,2018,8:11642.doi:10.1038/s41598-018-30051-2.
[6]KUMAR A,KUHN L T,BALBACH J.In-cell NMR:analysis of protein-small molecule interactions,metabolic processes,and protein phosphorylation[J/OL].Int J Mol Sci,2019,20.pii:E378.doi:10.3390/ijms20020378.
[7]LOU Y,YU Y,XU X,ZHOU S,SHEN H,FAN T,et al.Long non-coding RNA LUCAT1 promotes tumourigenesis by inhibiting ANXA2 phosphorylation in hepatocellular carcinoma[J].J Cell Mol Med,2019,23:1873-1884.
[8]CHEN C Y,LIN Y S,CHEN C H,CHEN Y J.Annexin A2-mediated cancer progression and therapeutic resistance in nasopharyngeal carcinoma[J/OL].J Biomed Sci,2018,25:30.doi:10.1186/s12929-018-0430-8.
[9]YUAN J,YANG Y,GAO Z,WANG Z,JI W,SONG W,et al.Tyr23 phosphorylation of AnxA2 enhances STAT3activation and promotes proliferation and invasion of breast cancer cells[J].Breast Cancer Res Treat,2017,164:327-340.
[10]BORTHWICK L A,NEAL A,HOBSON L,GERKEV,ROBSON L,MUIMO R.The annexin 2-S100A10complex and its association with TRPV6 is regulated by cAMP/PKA/CnA in airway and gut epithelia[J].Cell Calcium,2008,44:147-157.
[11]GABEL M,CHASSEROT-GOLAZ S.Annexin A2,an essential partner of the exocytotic process in chromaffin cells[J].J Neurochem,2016,137:890-896.
[12]CHASSEROT-GOLAZ S,VITALE N,UMBRECHT-JENCK E,KNIGHT D,GERKE V,BADER M F.Annexin 2 promotes the formation of lipid microdomains required for calcium-regulated exocytosis of dense-core vesicles[J].Mol Biol Cell,2005,16:1108-1119.
[13]AYALA-SANMARTIN J,GOUACHE P,HENRY J P.N-terminal domain of annexin 2 regulates Ca2+-dependent membrane aggregation by the core domain:a site directed mutagenesis study[J].Biochemistry,2000,39:15190-15198.
[14]BRANDHERM I,DISSE J,ZEUSCHNER D,GERKEV.cAMP-induced secretion of endothelial von Willebrand factor is regulated by a phosphorylation/dephosphorylation switch in annexin A2[J].Blood,2013,122:1042-1051.
[15]HOLTHENRICH A,GERKE V.Regulation of vonWillebrand factor secretion from endothelial cells by the annexin A2-S100A10 complex[J/OL].Int J Mol Sci,2018,19.pii:E1752.doi:10.3390/ijms19061752.
[16]HEDHLI N,FALCONE D J,HUANG B,CESARMAN-MAUS G,KRAEMER R,ZHAI H,et al.The annexin A2/S100A10 system in health and disease:emerging paradigms[J/OL].J Biomed Biotechnol,2012,2012:406273.doi:10.1155/2012/406273.
[17]BORTHWICK L A,MCGAW J,CONNER G,TAYLORC J,GERKE V,MEHTA A,et al.The formation of the cAMP/protein kinase A-dependent annexin 2-S100A10complex with cystic fibrosis conductance regulator protein(CFTR)regulates CFTR channel function[J].Mol Biol Cell,2007,18:3388-3397.
[18]AUKRUST I,HOLL?S H,STRAND E,EVENSEN L,TRAVéG,FLATMARK T,et al.The mRNA-binding site of annexin A2 resides in helices C-D of its domainⅣ[J].J Mol Biol,2007,368:1367-1378.
[19]VEDELER A,HOLL?S H,GRINDHEIM A K,RADDUM A M.Multiple roles of annexin A2 in posttranscriptional regulation of gene expression[J].Curr Protein Pept Sci,2012,13:401-412.
[20]AUKRUST I,ROSENBERG L A,ANKERUD M M,BERTELSEN V,HOLL?S H,SARASTE J,et al.Posttranslational modifications of Annexin A2 are linked to its association with perinuclear nonpolysomal mRNPcomplexes[J].FEBS Open Bio,2017,7:160-173.
[21]GRINDHEIM A K,HOLL?S H,RAMIREZ J,SARASTE J,TRAVéG,VEDELER A.Effect of serine phosphorylation and Ser25 phospho-mimicking mutations on nuclear localisation and ligand interactions of annexin A2[J].J Mol Biol,2014,426:2486-2499.
[22]CARON D,BOUTCHUENG-DJIDJOU M,TANGUAYR M,FAURE R L.Annexin A2 is SUMOylated on its N-terminal domain:regulation by insulin[J].FEBS Lett,2015,589:985-991.
[23]HAYES M J,SHAO D,BAILLY M,MOSS S E.Regulation of actin dynamics by annexin 2[J].EMBO J,2006,25:1816-1826.
[24]RESCHER U,LUDWIG C,KONIETZKO V,KHARITONENKOV A,GERKE V.Tyrosine phosphorylation of annexin A2 regulates Rho-mediated actin rearrangement and cell adhesion[J].J Cell Sci,2008,121(Pt 13):2177-2185.
[25]DE GRAAUW M,TIJDENS I,SMEETS M B,HENSBERGEN P J,DEELDER A M,VAN DE WATERB.Annexin A2 phosphorylation mediates cell scattering and branching morphogenesis via cofilin activation[J].Mol Cell Biol,2008,28:1029-1040.
[26]CUI H Y,WANG S J,MIAO J Y,FU Z G,FENG F,WUJ,et al.CD147 regulates cancer migration via direct interaction with Annexin A2 and DOCK3-β-cateninWAVE2 signaling[J].Oncotarget,2016,7:5613-5629.
[27]HAYES M J,MOSS S E.Annexin 2 has a dual role as regulator and effector of v-Src in cell transformation[J].JBiol Chem,2009,284:10202-10210.
[28]GABEL M,DELAVOIE F,ROYER C,TAHOULYT,GASMAN S,BADER M F,et al.Phosphorylation cycling of Annexin A2 Tyr23 is critical for calciumregulated exocytosis in neuroendocrine cells[J/OL].Biochim Biophys Acta Mol Cell Res,2019.pii:S0167-4889(18)30542-1.doi:10.1016/j.bbamcr.2018.12.013.
[29]TAURO B J,MATHIAS R A,GREENING D W,GOPALS K,JI H,KAPP E A,et al.Oncogenic H-ras reprograms Madin-Darby canine kidney(MDCK)cell-derived exosomal proteins following epithelial-mesenchymal transition[J].Mol Cell Proteomics,2013,12:2148-2159.
[30]BRONISZ A,WANG Y,NOWICKI M O,PERUZZIP,ANSARI K,OGAWA D,et al.Extracellular vesicles modulate the glioblastoma microenvironment via a tumor suppression signaling network directed by miR-1[J].Cancer Res,2014,74:738-750.
[31]PRASAD S,GUPTA S C,TYAGI A K.Reactive oxygen species(ROS)and cancer:role of antioxidative nutraceuticals[J].Cancer Lett,2017,387:95-105.
[32]ZOU Z,CHANG H,LI H,WANG S.Induction of reactive oxygen species:an emerging approach for cancer therapy[J].Apoptosis,2017,22:1321-1335..
[33]GRINDHEIM A K,HOLL?S H,RADDUM A M,SARASTE J,VEDELER A.Reactive oxygen species exert opposite effects on Tyr23 phosphorylation of the nuclear and cortical pools of annexin A2[J].J Cell Sci,2016,129:314-328.
[34]GRINDHEIM A K,VEDELER A.Extracellular vesicles released from cells exposed to reactive oxygen species increase annexin A2 expression and survival of target cells exposed to the same conditions[J/OL].Commun Integr Biol,2016,9:e1191715.doi:10.1080/19420889.2016.1191715.
[35]MOHAMMAD H S,KUROKOHCHI K,YONEYAMAH,TOKUDA M,MORISHITA A,JIAN G,et al.Annexin A2 expression and phosphorylation are up-regulated in hepatocellular carcinoma[J].Int J Oncol,2008,33:1157-1163.
[36]CHAUDHARY P,THAMAKE S I,SHETTY P,VISHWANATHA J K.Inhibition of triple-negative and Herceptin-resistant breast cancer cell proliferation and migration by Annexin A2 antibodies[J].Br J Cancer,2014,111:2328-2341.
[37]DATHE C,DAIGELER A L,SEIFERT W,JANKOWSKIV,MROWKA R,KALIS R,et al.Annexin A2 mediates apical trafficking of renal Na+-K+-2Cl-cotransporter[J].J Biol Chem,2014,289:9983-9997.
[38]DIAZ B,ELKBULI A,EHRHARDT J D Jr,MCKENNEY M,BONEVA D,HAI S.Pheochromocytoma-related cardiomyopathy presenting as broken heart syndrome:case report and literature review[J].Int J Surg Case Rep,2019,55:7-10.
[39]RADDUM A M,EVENSEN L,HOLL?S H,GRINDHEIMA K,LORENS J B,VEDELER A.DomainsⅠandⅣof annexin A2 affect the formation and integrity of in vitro capillary-like networks[J/OL].PLoS One,2013,8:e60281.doi:10.1371/journal.pone.0060281.
[40]LIMA E SILVA R,SHEN J,GONG Y Y,SEIDEL C P,HACKETT S F,KESAVAN K,et al.Agents that bind annexin A2 suppress ocular neovascularization[J].J Cell Physiol,2010,225:855-864.