Identification of pY19-caveolin-2 as a positive regulator of insulin-stimulated actin cytoskeleton-dependent mitogenesis.
Mitogenic regulation by caveolin-2 in response to insulin was investigated. Insulin triggered phosphorylation of caveolin-2 on tyrosine 19. Insulin increased the interaction between pY19-caveolin-2 and phospho-ERK, and that interaction was inhibited by a MEK inhibitor U0126. Insulin-induced interaction of caveolin-2 with phospho-ERK was prevented when tyrosine 19 is mutated to alanine. Insulin relocalized phospho-ERK and pY19-caveolin-2 to the nucleus and their nuclear co-localization was impaired by U0126. Down-regulation of caveolin-2 by caveolin-2 siRNA arrested the insulin-induced nuclear localization of ERK with no change in the insulin-stimulated ERK activation. Of consequence, the caveolin-2 siRNA attenuated the ERK-mediated c-Jun and cyclinD1 expression and DNA synthesis by insulin. In addition, actin cytoskeleton influenced the nuclear translocation of caveolin-2-ERK complex. Collectively, our findings underscore the importance of pY19-caveolin-2 with the spatial coordination by insulin in ERK-mediated mitogenic regulation of insulin signalling and indicate that the phosphorylation of pY19-caveolin-2 is required for actin cytoskeleton-dependent ERK nuclear import.
Department of Biochemistry, Division of Applied Life Science (BK21), Environmental Biotechnology National Core Research Center, Gyeongsang National University, Jinju, Korea.
Hayeong
H
Kwon
Kyuho
K
Jeong
Yunbae
Y
Pak
D000199:Actins / Q000378:metabolism*; D000818:Animals; D051243:Caveolin 2 / Q000172:deficiency / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects*; D002467:Cell Nucleus / Q000187:drug effects / Q000201:enzymology; D049109:Cell Proliferation / Q000187:drug effects; D003599:Cytoskeleton / Q000187:drug effects* / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005960:Glucosides / Q000494:pharmacology; D006801:Humans; D007328:Insulin / Q000494:pharmacology*; D051379:Mice; D017830:Octoxynol; D010766:Phosphorylation / Q000187:drug effects; D019000:Phosphotyrosine / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D011972:Receptor, Insulin / Q000378:metabolism; D012995:Solubility / Q000187:drug effects; D013329:Structure-Activity Relationship
D000199:Actins; D051243:Caveolin 2; D005960:Glucosides; D007328:Insulin; D016755:Proto-Oncogene Proteins c-jun; D034741:RNA, Small Interfering; D019000:Phosphotyrosine; C018619:octyl-beta-D-glucoside; D011092:Polyethylene Glycols; D017830:Octoxynol; C010615:Nonidet P-40; D011972:Receptor, Insulin; D048049:Extracellular Signal-Regulated MAP Kinases