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Frontiers in Biology

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Front. Biol.    2015, Vol. 10 Issue (3) : 195-202    https://doi.org/10.1007/s11515-015-1352-4
REVIEW
Csk-homologous kinase (Chk/Matk): a molecular policeman suppressing cancer formation and progression
Gahana Advani1,Anderly C. Chueh2,Ya Chee Lim1,Amardeep Dhillon3,Heung-Chin Cheng1,*()
1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria 3010, Australia
2. ACRF Chemical Biology Division, The Walter and Eliza Hall Institute for Medical Research, Royal Melbourne Hospital, and Department of Medical Biology, University of Melbourne, Parkville, Victoria 3052, Australia
3. Peter MacCallum Cancer Research Institute, St. Andrews Place, East Melbourne, Victoria, Australia
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Abstract

Aberrant activation of Src-family tyrosine kinases (SFKs) directs initiation of metastasis and development of drug resistance in multiple solid tumors and hematological cancers. Since oncogenic mutations of SFKs are rare events, aberrant activation of SFKs in cancer is likely due to dysregulation of the two major upstream inhibitors: C-terminal Src kinase (Csk) and its homolog Csk-homologous kinase (Chk/Matk). Csk and Chk/Matk inhibit SFKs by selectively phosphorylating the inhibitory tyrosine residue at their C-terminal tail. Additionally, Chk/Matk can also employ a non-catalytic inhibitory mechanism to inhibit multiple active forms of SFKs, suggesting that Chk/Matk is a versatile inhibitor capable of constraining the activity of multiple active forms of SFKs. Mounting evidence suggests that Chk/Matk is a potential tumor suppressor downregulated by epigenetic silencing and/or missense mutations in several cancers such as colorectal and lung carcinoma. In spite of the potential significance of Chk/Matk in cancer, little is known about its structure and regulation. This review focuses on the mechanisms by which Chk/Matk expression and activity is downregulated in cancers. Specifically, we assessed the evidence demonstrating downregulation of Chk/Matk by epigenetic silencing and missense mutations in cancers. The other focus is the tumor suppressive mechanism of Chk/Matk. The final focus of the review is on the clinical applications of the investigations into the mechanism of epigenetic silencing of Chk/Matk expression and the tumor suppressive mechanism of Chk/Matk; specifically we discussed how they can benefit the development of biomarkers for early diagnosis of cancers and specific SFK inhibitors for use as cancer therapeutics.
Keywords tumour suppressor      protein tyrosine kinase      Src-family kinases      CSK      CHK/Matk      colon cancer     
Corresponding Author(s): Heung-Chin Cheng   
Just Accepted Date: 15 February 2015   Online First Date: 30 March 2015    Issue Date: 23 June 2015
 Cite this article:   
Gahana Advani,Anderly C. Chueh,Ya Chee Lim, et al. Csk-homologous kinase (Chk/Matk): a molecular policeman suppressing cancer formation and progression[J]. Front. Biol., 2015, 10(3): 195-202.
 URL:  
https://academic.hep.com.cn/fib/EN/10.1007/s11515-015-1352-4
https://academic.hep.com.cn/fib/EN/Y2015/V10/I3/195
Fig.1  The human Chk/Matk gene. (A) Structure of the Chk/Matk gene. The Chk/Matk gene contains 14 exons of which 13 are protein coding. The transcription initiation site is located 360 bp upstream of the translation initiation site. Shaded boxes are exons which are transcribed but not translated. (B) The three transcripts encoded by the Chk/Matk gene. (C) Sequences of the N-terminal segment of the three Chk/Matk isoforms. Among them, isoform two does not contain the first exon and isoform three has a different promoter and a different N-terminal region coded for by exon 1. The sequences in the three putative isoforms (panel C) and the exons from which these sequences are derived (panel B) are presented in the same colors.
Fig.2  The non-catalytic inhibitory mechanism of Chk/Matk and a model of Chk/Matk structure showing the locations of cancer-associated missense mutations. (A) A schematic diagram depicting how SFKs are activated to form multiple active forms by binding to the ligands of the SH2 and SH3 domains and by autophosphorylation. Biochemical analysis demonstrated that Chk/Matk but not Csk can employ the non-catalytic inhibitory mechanism to bind and inhibit all the active forms of SFKs. Dephosphorylation by specific phosphatases and dissociation of the ligands covert these active forms of SFKs to the unphosphorylated/unliganded form. Csk and Chk/Matk can induce this form of SFKs to adopt the stable inactive conformation by phosphorylation of the C-terminal tail tyrosine. (B) A schematic diagram showing the similarities and differences of CSK and the two isoforms of Chk/Matk p52Chk/Matk and p56Chk/Matk. (C). Using the Csk structure as the model, the locations of key residues found to undergo missense mutation in cancers are shown.
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