| First Author | Mahajan K | Year | 2010 |
| Journal | PLoS One | Volume | 5 |
| Issue | 3 | Pages | e9646 |
| PubMed ID | 20333297 | Mgi Jnum | J:158889 |
| Mgi Id | MGI:4440773 | Doi | 10.1371/journal.pone.0009646 |
| Citation | Mahajan K, et al. (2010) Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation. PLoS One 5(3):e9646 |
| abstractText | 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. |
