Nature子刊上的akt pathway的信号通路图

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AKT大家一定不陌生，即蛋白激酶B，细胞凋亡重要因子。本文精选了Nature 子刊、世界公认的顶尖综述期刊——Nature Reviews Cancer上关于akt pathway的信号通路图。

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Activation of class IA phosphatidylinositol 3-kinases (PI3Ks) occurs through stimulation of receptor tyrosine kinases (RTKs) and the concomitant assembly of receptor–PI3K complexes. These complexes localize at the membrane where the p110 subunit of PI3K catalyses the conversion of PtdIns(4,5)P2 (PIP2) to PtdIns(3,4,5)P3 (PIP3). PIP3 serves as a second messenger that helps to activate AKT. Through phosphorylation, activated AKT mediates the activation and inhibition of several targets, resulting in Cell ular growth, survival and proliferation through various mechanisms. Additionally, PI3K has been shown to regulate the activity of other cellular targets, such as the serum and glucocorticoid-inducible kinase (SGK), the small GTP-binding proteins RAC1 and CDC42, and protein kinase C (PKC), in an AKT-independent manner through poorly characterized mechanisms. The activity of these targets leads to survival, cytoskeletal rearrangement and transformation. GSK3 &beta; lycogen synthase kinase-3; NF-&kappa;B, nuclear factor of &kappa;B; PDK1/2, 3-phosphoinositide-dependent protein kinase 1/2.

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Autophosphorylation of ligand-activated receptor tyrosine kinases (RTKs) causes recruitment of inactive heterodimeric class IA phosphatidylinositol 3-kinases (PI3Ks) through the interaction of phosphotyrosine residues on the receptor and SRC-homology 2 (SH2) domains on the PI3K p85 regulatory subunit, or the adaptor proteins IRS1 and IRS2. IRS1 and IRS2 are phosphorylated by the activated receptor, generating docking sites for the SH2 domains of p85 and inducing proper assembly of the signalling complex. These SH2–phosphotyrosine interactions bring PI3K in close proximity to its substrate at the plasma membrane and relieve the inhibitory action of p85 on the p110 catalytic subunit, which is then free to convert PtdIns(4,5)P2 (PIP2) into PtdIns(3,4,5)P3 (PIP3). Alternatively, binding of PI3K to activated RAS can also stabilize its membrane localization and activate the catalytic domain. This occurs by recruitment of the adaptor proteins SHC, GRB2 and GAB2 to activated RTKs. C2, C2 domain; CD, catalytic domain; p85 BD, p85-binding domain; RBD, RAS-binding domain.

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Activation of AKT is initiated by membrane translocation, which occurs after cell stimulation and PtdIns(3,4,5)P3 (PIP3) production. Localization of AKT to the plasma membrane is accomplished by an interaction between its pleckstrin-homology (PH) domain and PIP3. At the membrane, association with carboxy-terminal modulator protein (CTMP) prevents AKT from becoming phosphorylated and fully active. Phosphorylation of CTMP by an as yet unidentified kinase releases CTMP from AKT and allows AKT to be phosphorylated by PDK1 and PDK2 at Thr308 and Ser473, respectively. Phosphorylation at these two sites causes full activation of AKT. C2, C2 domain; CD, catalytic domain; p85 BD, p85-binding domain.

Nature Reviews Cancer是肿瘤研究领域内的公认顶级期刊，其影响因子高达37.2，在上面发表的文章含金量相当高。不过目前中国内地在该期刊上发表的文章数屈指可数。