Syndecan-4以PKCα依赖的方式调节内皮细胞中mTOR复合物2的亚细胞定位和Akt激活。
Syndecan-4 regulates subcellular localization of mTOR Complex2 and Akt activation in a PKCalpha-dependent manner in endothelial cells.
作者信息
Partovian Chohreh, Ju Rong, Zhuang Zhen W, Martin Kathleen A, Simons Michael
机构信息
Angiogenesis Research Center, Dartmouth Medical School, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA.
出版信息
Mol Cell. 2008 Oct 10;32(1):140-9. doi: 10.1016/j.molcel.2008.09.010.
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.
雷帕霉素哺乳动物靶蛋白（mTOR）的活性受两种功能不同的复合物mTORC1和mTORC2组装的调节。在syndecan - 4（S4）基因缺失的内皮细胞中，mTORC2活性降低，导致Akt激活减少，而mTORC1活性增加。在总细胞裂解物中，rictor、mLST8和mSin - 1的水平未发生变化，但在S4（- / -）内皮细胞的脂筏中降低，PKCalpha的水平也是如此。在S4（- / -）细胞中表达肉豆蔻酰化的PKCalpha可恢复脂筏中rictor、mLST8和mSin - 1的存在，并挽救Akt磷酸化。敲低PKCalpha可模拟S4缺失对mTORC2定位和Akt激活的影响。S4（- / -）内皮细胞中mTORC2活性降低导致S4（- / -）小鼠中FoxO1/3a和eNOS磷酸化减少、内皮细胞大小减小以及动脉血压升高。因此，PKCalpha依赖S4靶向质膜是mTORC2组分募集到脂筏和Akt激活所必需的。
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