Rebecca Cook
Faculty Member
Last active: 4/15/2019

Ack1 mediated AKT/PKB tyrosine 176 phosphorylation regulates its activation.

Mahajan K, Coppola D, Challa S, Fang B, Chen YA, Zhu W, Lopez AS, Koomen J, Engelman RW, Rivera C, Muraoka-Cook RS, Cheng JQ, Schönbrunn E, Sebti SM, Earp HS, Mahajan NP
PLoS One. 2010 5 (3): e9646

PMID: 20333297 · PMCID: PMC2841635 · DOI:10.1371/journal.pone.0009646

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.

MeSH Terms (15)

Animals Breast Neoplasms Cell Membrane Disease Progression Female Humans Male Mice Mice, Transgenic Phosphorylation Prostatic Intraepithelial Neoplasia Protein-Tyrosine Kinases Protein Structure, Tertiary Proto-Oncogene Proteins c-akt Tyrosine

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