Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation

The Akt/PKB kinase is a key signaling component of one of the most frequently activated pathways in Cancer and is a major target of Cancer drug development. Most studies have focused on its activation by Receptor Tyrosine Kinase (RTK) mediated Phosphatidylinositol-3-OH kinase (PI3K) activation or loss of Phosphatase and Tensin homolog (PTEN). We have uncovered that growth factors binding to RTKs lead to activation of a non-receptor tyrosine kinase, Ack1 (also known as ACK or TNK2), which directly phosphorylates Akt at an evolutionarily conserved tyrosine 176 in the kinase domain. Tyr176-phosphorylated Akt localizes to the plasma membrane and promotes Thr308/Ser473-phosphorylation leading to Akt activation. Mice expressing activated Ack1 specifically in the prostate exhibit Akt Tyr176-phosphorylation and develop murine prostatic intraepithelial neoplasia (mPINs). Further, expression levels of Tyr176-phosphorylated-AKT and Tyr284-phosphorylated-Ack1 were positively correlated with the severity of disease progression, and inversely correlated with the survival of breast Cancer patients. Thus, RTK/Ack1/Akt pathway provides a novel target for drug discovery.