The AKT/PKB kinase is activated by PI3K activation or loss of PTEN. Interestingly, about a third of the breast and prostate tumors and majority of the pancreatic tumors that exhibit AKT activation retain normal PTEN and PI3K activity.
Novel AKT Tyr176-phosphorylation, mediated by ACK1
We have uncovered a novel signaling mechanism wherein ACK1 directly phosphorylated AKT at Tyr176. For membrane localization, AKT anchors to Phosphatidylinositol (3,4,5)-trisphosphate or PIP3. However, Tyr176-phosphorylated AKT bound another membrane phospholipid, phosphatidic acid (PA). Further, Tyr176-phosphorylated AKT translocated to the membrane leading to its Ser473-phosphorylation and kinase activation.
AKT Tyr176-phosphorylation in Prostate and breast cancer
We generated ACK1 transgenic mice that not only exhibited AKT Tyr176-phosphorylation but also developed murine prostatic intraepithelial neoplasia (mPINs) and carcinomas.
The most significant role of pY176-AKT was observed in progression of breast cancer. The expression levels of pY176-AKT and activated ACK1 were positively correlated with the severity of breast cancer progression, and inversely correlated with the survival of patients.