Syndecan-4 regulates subcellular localization of mTOR Complex2 and Akt activation in a PKCalpha-dependent manner in endothelial cells.
Mammalian target of rapamycin (mTOR) activity is regulated by assembly of two functionally distinct complexes, mTORC1 and mTORC2. In syndecan-4 (S4) null endothelial cells, mTORC2 activity is reduced, resulting in decreased Akt activation, while mTORC1 activity is increased. Levels of rictor, mLST8, and mSin-1 are unchanged in total cell lysates but decreased in the rafts of S4(-/-) endothelial cells, as is the level of PKCalpha. Expression of myristoylated-PKCalpha in S4(-/-) cells restores rictor, mLST8, and mSin-1 presence in the rafts and rescues Akt phosphorylation. PKCalpha knockdown mimics the effect of S4 deletion on mTORC2 localization and Akt activation. Reduced mTORC2 activity in S4(-/-) endothelial cells results in decreased FoxO1/3a and eNOS phosphorylation, decreased endothelial cell size, and increased arterial blood pressure in S4(-/-) mice. Thus, S4-dependent targeting of PKCalpha to the plasma membrane is required for recruitment of mTORC2 components to the rafts and Akt activation.
Partovian
Chohreh
C
Angiogenesis Research Center, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
Ju
Rong
R
Zhuang
Zhen W
ZW
Martin
Kathleen A
KA
Simons
Michael
M
D000818:Animals; D001693:Biological Transport, Active; D002460:Cell Line; D002478:Cells, Cultured; D042783:Endothelial Cells / Q000187:drug effects / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006133:Growth Substances / Q000494:pharmacology; D021962:Membrane Microdomains / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D053671:Syndecan-4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*
D006133:Growth Substances; C508306:Sdc4 protein, mouse; D053671:Syndecan-4; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C496630:Prkca protein, mouse; D051571:Protein Kinase C-alpha