Ack1 Mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation

Kiran Mahajan, Domenico Coppola, Sridevi Challa, Bin Fang, Y. Ann Chen, Weiwei Zhu, Alexis S. Lopez, John Koomen, Robert W. Engelman, Charlene Rivera, Rebecca S. Muraoka-Cook, Jin Q. Cheng, Ernst Schönbrunn, Said M. Sebti, H. Shelton Earp, Nupam P. Mahajan

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102 Scopus citations

Abstract

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.

Original languageEnglish
Article numbere9646
JournalPloS one
Volume5
Issue number3
DOIs
StatePublished - 2010

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