Syndecan-4 Regulates Subcellular Localization of MTOR Complex2 and Akt Activation in a PKCalpha-dependent Manner in Endothelial Cells

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2008 Oct 15

PMID 18851840

Citations 67

Authors

Chohreh Partovian

Rong Ju

Zhen W Zhuang

Kathleen A Martin

Michael Simons

Affiliations

Soon will be listed here.

Abstract

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.

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