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.
Mesh Terms:
Animals, Biological Transport, Active, Cell Line, Cells, Cultured, Endothelial Cells, Enzyme Activation, Growth Substances, Membrane Microdomains, Mice, Mice, Knockout, Models, Biological, Protein Kinase C-alpha, Proto-Oncogene Proteins c-akt, Syndecan-4, Trans-Activators, Transcription Factors
Mol. Cell
Date: Oct. 10, 2008
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