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.

Detection of AKT Tyr176 phosphorylation
PI3K-ndependent AKT activation in breast cancer: (A) TMA stained with pTyr284-ACK1 and pTyr176-AKT antibodies. (B) Increasing expression of pTyr284-ACK1 in later stages of breast cancer. (C) Increasing expression of pTyr176-AKT in later stages of breast cancer. (D) Kaplan–Meier analysis shows that individuals that have moderate to strong staining of pTyr284-ACK1 or pTyr176-AKT have significantly lower probability of survival.