PI3K-Akt

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PI3K-Akt signaling pathway

 

Phosphatidylinositol 3-kinases (PI 3-kinases or PI3Ks) are a family of enzymes involved in cellular functions such as cell growth, proliferation, differentiation, motility, survival and intracellular trafficking, which in turn are involved in cancer. In PI3K family, PI3K type Ⅰ has been widely researched. In mammalian cells there are two subtypes: ⅠA and ⅠB, both of which receive signals from Receptor tyrosine kinase (RTK) and G protein coupled receptors (GPCRs). Type ⅠA is a dimer and composed of catalyzing subunit p110 and regulatory subunit p85. It possesses double activities of lipid kinase and protein kinase. PI3K can be activated by two pathways: the first one is that it reacts with growth factor receptors or adaptor proteins which have phosphorylated tyrosine residues, then conformational changes occur to the dimmers and lead to activation of PI3K; the second one is that direct binding of PI3K to p110 via Ras leads to activation of PI3K. Activated PI3K gives birth to PIP3, a secondary messenger on the plasma membrane. PIP3 binds signal proteins Akt and PDK1 (phosphoinositide-dependent kinase-1) which contain PH domain, then PDK1 phosphorylates Ser308 of Akt and leads to activation of Akt. Akt can also be activated by that PDK2 (e.g. integrin-linked kinase, ILK) phosphorylates Thr473 of Akt. Activated Akt then activates or inhibits downstream target proteins such as Bad, Caspase-9, NF-кB, GSK-3, FKHR, p21Cipl and p27Kipl etc to regulate cellular proliferation, differentiation, apoptosis and migration etc.

The activity of PI3K-Akt signaling pathway is down-regulated by PTEN (phosphatase and tensin homolog deleted on chromosome ten) and SHIP (SH2-containing inositol 5-phosphatase). They respectively degrade PIP3 by eliminating phosphoric acid of 3’ and 5’ end and turning them into PI(4,5)P2 and PI(3,4)P2. After treatment with inhibitors of phosphorylase, intracellular activity and phosphorylation of Akt both increase. Akt can be inactivated by a kind of C terminal mediation protein (CTMP). CTMP is able to bind Akt and stop downstream signal transduction by inhibiting phosphorylation of Akt. Overexpression of CTMP can revert the phenotype of v-Akt transfected cells. Heat-shock protein can bind Akt and prevent its inactivation from dephosphorylation of PP2A phosphorylase.

PI3K-Akt signaling pathway and tumor

PI3K abnormality and cell transformation:

Activity of PI3K is closely related with breast cancer, lung cancer, melanoma and lymphoma etc. In human tumors, genes that encode key molecules in PI3K-Akt signaling pathway have structural changes. For example, tunmor cell-derived mutants of p85 regulatory subunit, truncated p65-PI3K (short of iSH2 domain and C terminal SH2 domain) can induce constitutive activation of PI3K and cell transformation. In colorectal cancer and ovarian cancer, loss and mutation in iSH2 domain of p85αgene leads to activation of PI3K. In non-small cell lung cancer (NSCLC), prostate cancer and intestinal cancer there exists continuous activation and expression enhancement of PI3K, Akt, NF-kappaB/p65 etc and cell proliferation is obviously inhibited after suppression PI3K activity with features of blockade of cell cycle, reduction of expression of G1-stage CyclinD1 and CDK4 and phosphorylation of Rb etc. This kind of blockade of cell cycle can be recovered by intracellular expression of active Akt and downstream p70S6K. It’s similar to the amplification of non-mutant ERBB2RTK in breast cancer. Thus it’s speculated that overexpressions of normal-structure proteins might lead to cell transformation.