The activation mechanism of ACK1 (activated Cdc42-associated tyrosine kinase 1)

The Biochemical Journal
Qiong LinWannian Yang

Abstract

ACK [activated Cdc42 (cell division cycle 42)-associated tyrosine kinase; also called TNK2 (tyrosine kinase, non-receptor, 2)] is activated in response to multiple cellular signals, including cell adhesion, growth factor receptors and heterotrimeric G-protein-coupled receptor signalling. However, the molecular mechanism underlying activation of ACK remains largely unclear. In the present study, we demonstrated that interaction of the SH3 (Src homology 3) domain with the EBD [EGFR (epidermal growth factor receptor)-binding domain] in ACK1 forms an auto-inhibition of the kinase activity. Release of this auto-inhibition is a key step for activation of ACK1. Mutation of the SH3 domain caused activation of ACK1, independent of cell adhesion, suggesting that cell adhesion-mediated activation of ACK1 is through releasing the auto-inhibition. A region at the N-terminus of ACK1 (Leu10-Leu14) is essential for cell adhesion-mediated activation. In the activation of ACK1 by EGFR signalling, Grb2 (growth-factor-receptor-bound protein 2) mediates the interaction of ACK1 with EGFR through binding to the EBD and activates ACK1 by releasing the auto-inhibition. Furthermore, we found that mutation of Ser445 to proline caused constitutive activat...Continue Reading

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Citations

Apr 20, 2013·Cancer Letters·Kiran Mahajan, Nupam P Mahajan
Dec 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Sijia WuHaley E Melikian
May 26, 2017·The Journal of Biological Chemistry·George J N TetleyDarerca Owen
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Jun 21, 2019·Developmental Dynamics : an Official Publication of the American Association of Anatomists·Katrina R FritzL Bruno Ruest
Nov 28, 2019·BioMed Research International·Xia LiuBaolin Han
Aug 30, 2018·Biochemical Society Transactions·Darerca Owen, Helen R Mott
Jan 24, 2021·Journal of Clinical Laboratory Analysis·Anqing ZhangRui Tian
Nov 21, 2020·International Journal of Molecular Sciences·Justin F CreedenRobert E McCullumsmith

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