The AKT/PKB kinase is activated by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). Interestingly, about a third of the breast and prostate tumors and majority of the pancreatic tumors that exhibit AKT activation, but, retain normal PTEN and PI3K activity. The mechanisms of AKT activation with normal PTEN and PI3K activity is poorly understood.
Novel AKT phosphorylation, Tyrosine176-phosphorylation, mediated by ACK1
We have uncovered a novel signaling mechanism wherein ACK1 directly phosphorylates AKT at tyrosine176. 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, AKT that is Tyr176-phosphorylated can translocate to the membrane and undergo Ser473-phosphorylation and thus kinase activation even when PI3K is mutated/inactive.
AKT Tyr176-phosphorylation in Prostate cancer
The primary physiological outcome of Ack1 mediated AKT Tyr176-phosphorylation is the suppression of apoptotic genes expression and promotion of mitotic progression. We generated ACK1 transgenic mice that not only exhibited AKT Tyr176-phosphorylation but also developed murine prostatic intraepithelial neoplasia or PINs and carcinomas.
AKT Tyr-phosphorylation in Breast Cancer
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. The figures on right shows: (A) TMA sections representing different breast cancer stages 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 with breast cancer that have moderate to strong staining (>4) of pTyr284-ACK1 have a lower probability of survival. (E) Kaplan–Meier analysis of the breast cancer patients that have moderate to strong staining (>4) of pTyr176-AKT have significantly lower probability of survival.