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 activation of ACK1. Taken together, our studies have revealed a novel molecular mechanism underlying activation of ACK1.
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Research Article|
June 27 2012
The activation mechanism of ACK1 (activated Cdc42-associated tyrosine kinase 1)
Qiong Lin;
Qiong Lin
1
*School of Medical Sciences and Laboratory Medicine, Jiangsu University, Zhenjiang 212013, China
†Weis Center for Research, Geisinger Clinic, 100 N. Academy Avenue, Danville, PA 17822, U.S.A.
1Correspondence may be addressed to either of these authors (qlin1@geisinger.edu or wyang1@geisinger.edu).
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Jian Wang;
Jian Wang
†Weis Center for Research, Geisinger Clinic, 100 N. Academy Avenue, Danville, PA 17822, U.S.A.
‡Laboratory of Molecular Biology of Medicine, Beijing Institute of Biotechnology, Beijing 100850, China
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Chandra Childress;
Chandra Childress
†Weis Center for Research, Geisinger Clinic, 100 N. Academy Avenue, Danville, PA 17822, U.S.A.
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Wannian Yang
Wannian Yang
1
†Weis Center for Research, Geisinger Clinic, 100 N. Academy Avenue, Danville, PA 17822, U.S.A.
1Correspondence may be addressed to either of these authors (qlin1@geisinger.edu or wyang1@geisinger.edu).
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Publisher: Portland Press Ltd
Received:
August 29 2011
Revision Received:
April 18 2012
Accepted:
May 03 2012
Accepted Manuscript online:
May 03 2012
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 445 (2): 255–264.
Article history
Received:
August 29 2011
Revision Received:
April 18 2012
Accepted:
May 03 2012
Accepted Manuscript online:
May 03 2012
Citation
Qiong Lin, Jian Wang, Chandra Childress, Wannian Yang; The activation mechanism of ACK1 (activated Cdc42-associated tyrosine kinase 1). Biochem J 15 July 2012; 445 (2): 255–264. doi: https://doi.org/10.1042/BJ20111575
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