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Cell Signal. 2013 Jan;25(1):101-5. doi: 10.1016/j.cellsig.2012.09.007. Epub 2012 Sep 10.

Syndecan 4 regulation of PDK1-dependent Akt activation.

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Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.


The phosphatidylinositol 3 kinase (Pi3K)/Akt pathway is a major regulator of cell growth, proliferation, metabolism, survival, and angiogenesis. Despite extensive study, a thorough understanding of the modulation and regulation of this pathway has remained elusive. We have previously demonstrated that syndecan 4 (S4) regulates the intracellular localization of mTORC2, thus altering phosphorylation of Akt at serine473 (Ser473), one of two critical phosphorylation sites essential for the full activation of Akt [1]. Here we report that S4 also regulates the phosphorylation of Akt at threonine308 (Thr308), the second phosphorylation site required for the full Akt activation. A deletion of S4 resulted in lower levels of Thr308 phosphorylation both in vitro and in vivo. Furthermore, a deletion or knockdown of the S4 effector molecule PKCα led to a similar reduction in phosphorylation of Thr308 while overexpression of myristoylated PKCα rescued AktThr308 phosphorylation in endothelial cells lacking S4. Finally, PAK1/2 is also recruited to the rafts by the S4-PKCα complex and is required for AKT activation.

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