Yale Cardiovascular Research Center, Section of Cardiovascular Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
Cell Signal. 2013 Jan;25(1):101-5. doi: 10.1016/j.cellsig.2012.09.007. Epub 2012 Sep 10.
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.
磷脂酰肌醇 3 激酶（PI3K）/Akt 途径是细胞生长、增殖、代谢、存活和血管生成的主要调节剂。尽管进行了广泛的研究，但对该途径的调节和调控仍未完全了解。我们之前已经证明 syndecan 4（S4）调节 mTORC2 的细胞内定位，从而改变 Akt 在丝氨酸 473（Ser473）的磷酸化，这是 Akt 完全激活所必需的两个关键磷酸化位点之一[1]。在这里，我们报告 S4 还调节 Akt 在苏氨酸 308（Thr308）的磷酸化，这是 Akt 完全激活所需的第二个磷酸化位点。S4 的缺失导致体外和体内的 Thr308 磷酸化水平降低。此外，S4 效应分子 PKCα 的缺失或敲低导致 Thr308 磷酸化的类似减少，而过表达肉豆蔻酰化的 PKCα 可挽救缺乏 S4 的内皮细胞中 AktThr308 的磷酸化。最后，PAK1/2 也被 S4-PKCα 复合物募集到筏中，并需要 AKT 激活。
