Ack1 Mediated AKT/PKB Tyrosine 176 Phosphorylation Regulates Its Activation
Public Deposited- Creator
- Mahajan, Kiran
- Coppola, Domenico
- Challa, Sridevi
- Fang, Bin
- Chen, Y. Ann
- Zhu, Weiwei
- Lopez, Alexis S.
- Koomen, John
- Engelman, Robert W.
- Rivera, Charlene
- Muraoka-Cook, Rebecca S.
- Cheng, Jin Q.
- Schönbrunn, Ernst
- Sebti, Said M.
- Earp, H. Shelton
- Mahajan, Nupam P.
- 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.
- Date of publication
- 2010
- Keyword
- DOI
- Identifier
- Onescience id: ab367176573a9ff0b64a8b309b564443bc938fe5
- Publisher DOI: https://doi.org/10.1371/journal.pone.0009646
- PMID: 20333297
- PMCID: PMC2841635
- Resource type
- Article
- Rights statement
- In Copyright
- Journal title
- PloS One
- Journal volume
- 5
- Journal issue
- 3
- Page start
- e9646
- Language
- English
- ISSN
- 1932-6203
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