Phosphoprotein Phosphatase 1 Isoforms Alpha and Gamma Respond Differently to Prodigiosin Treatment and Present Alternative Kinase Targets in Melanoma Cells  

作　　者：Margarida Fardilha Joao Figueiredo Margarita Espona-Fiedler Juliana Felgueiras Luis Korrodi-Gregorio Sara L.C.Esteves Sandra Rebelo Odete A.B.da Cruz Silva Edgar da Cruz e Silva Ricardo Perez-Tomas 

机构地区：[1]Laboratory of Signal Transduction,Centre for Cell Biology,Biology Department and Health Sciences Department,University of Aveiro,Aveiro,Portugal [2]Department of Pathology and Experimental Therapeutics,Cancer Cell Biology Research Group,University of Barcelona,Barcelona,Spain [3]Laboratory of Neuroscience,Centre for Cell Biology,Biology Department and Health Sciences Department,University of Aveiro,Aveiro,Portugal

出　　处：《Journal of Biophysical Chemistry》2014年第2期67-77,共11页生物物理化学（英文）

基　　金：supported by grants from Fundacao para a Ciencia e Tecnologia(FCT)of the Portuguese Ministry of Science and Higher Education(PTDC/DTP-PIC/0460/2012);by FEDER through Eixo I do Programa Operacional Fatores de Competitividade(POFC)(FCOMP-01-0124-FEDER-028692)co-funded by QREN

摘　　要：Reversible protein phosphorylation is a central regulatory mechanism of cell function. Deregulation of the balanced actions of protein kinases and phosphatases has been frequently associated with several pathological conditions, including cancer. Many studies have already addressed the role of protein kinases misregulation in cancer. However, much less is known about protein phosphatases influence. Phosphoprotein Phosphatase 1 (PPP1) is one of the major serine/threonine protein phosphatases who has three catalytic isoforms: PPP1CA, PPP1CB, and PPP1CC. Its function is achieved by binding to regulatory subunits, known as PPP1-interacting proteins (PIPs), which may prefer a catalytic isoform. Also, some inhibitors/enhancers may exhibit isoform specificity. Here we show that, prodigiosin (PG), a molecule with anticancer properties, promotes the formation of PPP1CA-AKT complex and not of PPP1CC-MAPK complex. Both, AKT and MAPK, are well-known PIPs from two pathways that crosstalk and regulate melanoma cells survival. In addition, the analysis performed using surface plasmon resonance (SPR) technology indicates that PPP1 interacts with obatoclax (OBX), a drug that belongs to the same family of PG. Overall, these results suggest that PG might, at least in part, act through PPP1C/PIPs. Also, this study is pioneer in demonstrating PPP1 isoform-specific modulation by small molecules.Reversible protein phosphorylation is a central regulatory mechanism of cell function. Deregulation of the balanced actions of protein kinases and phosphatases has been frequently associated with several pathological conditions, including cancer. Many studies have already addressed the role of protein kinases misregulation in cancer. However, much less is known about protein phosphatases influence. Phosphoprotein Phosphatase 1 (PPP1) is one of the major serine/threonine protein phosphatases who has three catalytic isoforms: PPP1CA, PPP1CB, and PPP1CC. Its function is achieved by binding to regulatory subunits, known as PPP1-interacting proteins (PIPs), which may prefer a catalytic isoform. Also, some inhibitors/enhancers may exhibit isoform specificity. Here we show that, prodigiosin (PG), a molecule with anticancer properties, promotes the formation of PPP1CA-AKT complex and not of PPP1CC-MAPK complex. Both, AKT and MAPK, are well-known PIPs from two pathways that crosstalk and regulate melanoma cells survival. In addition, the analysis performed using surface plasmon resonance (SPR) technology indicates that PPP1 interacts with obatoclax (OBX), a drug that belongs to the same family of PG. Overall, these results suggest that PG might, at least in part, act through PPP1C/PIPs. Also, this study is pioneer in demonstrating PPP1 isoform-specific modulation by small molecules.

关 键 词：Phosphoprotein Phosphatase 1 Catalytic Subunit Surface Plasmon Resonance Mitogen-Activated Protein Kinase V-Akt Murine Thymoma Viral Oncogene Glycogen Synthase Kinase 3 

分 类 号：R73[医药卫生—肿瘤]