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Shepherding AKT and androgen receptor by Ack1 tyrosine kinase
Author(s) -
Mahajan Kiran,
Mahajan Nupam P.
Publication year - 2010
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.22162
Subject(s) - receptor tyrosine kinase , cancer research , protein kinase b , microbiology and biotechnology , biology , tyrosine kinase , androgen receptor , proto oncogene tyrosine protein kinase src , platelet derived growth factor receptor , phosphorylation , ror1 , tyrosine phosphorylation , signal transduction , receptor , cancer , prostate cancer , growth factor , biochemistry , genetics
Ack1 (also known as ACK, TNK2, or activated Cdc42 kinase) is a structurally unique non‐receptor tyrosine kinase that is expressed in diverse cell types. It integrates signals from plethora of ligand‐activated receptor tyrosine kinases (RTKs), for example, MERTK, EGFR, HER2, PDGFR and insulin receptor to initiate intracellular signaling cascades. Ack1 transduces extracellular signals to cytosolic and nuclear effectors such as the protein kinase AKT/PKB and androgen receptor (AR), to promote cell survival and growth. While tyrosine phosphorylation of AR at Tyr267 regulates androgen‐independent recruitment of AR to the androgen‐responsive enhancers and transcription of AR target genes to drive prostate cancer progression, phosphorylation of an evolutionarily conserved Tyrosine 176 in the kinase domain of AKT is essential for mitotic progression and positively correlates with breast cancer progression. In contrast to AR and AKT, Ack1‐mediated phosphorylation of the tumor suppressor Wwox at Tyr287 lead to rapid Wwox polyubiquitination followed by degradation. Thus, by its ability to promote tumor growth by negatively regulating tumor suppressor such as Wwox and positively regulating pro‐survival factors such as AKT and AR, Ack1 is emerging as a critical player in cancer biology. In this review, we discuss recent advances in understanding the physiological functions of Ack1 signaling in normal cells and the consequences of its hyperactivation in various cancers. J. Cell. Physiol. 224: 327–333, 2010. © 2010 Wiley‐Liss, Inc.