Skip to main content
SpringerLink
Log in

Csk-homologous kinase (Chk/Matk): a molecular policeman suppressing cancer formation and progression

  • Review
  • Published:
Frontiers in Biology

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 noncatalytic 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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  • Avraham S, Jiang S, Ota S, Fu Y, Deng B, Dowler L L, White R A, Avraham H (1995). Structural and functional studies of the intracellular tyrosine kinase MATK gene and its translated product. J Biol Chem, 270(4): 1833–1842

    Article  CAS  PubMed  Google Scholar 

  • Barkho S, Pierce L C, McGlone M L, Li S, Woods V L Jr, Walker R C, Adams J A, Jennings P A (2013). Distal loop flexibility of a regulatory domain modulates dynamics and activity of C-terminal SRC kinase (csk). PLOS Comput Biol, 9(9): e1003188

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bennett B D, Cowley S, Jiang S, London R, Deng B, Grabarek J, Groopman J E, Goeddel D V, Avraham H (1994). Identification and characterization of a novel tyrosine kinase from megakaryocytes. J Biol Chem, 269(2): 1068–1074

    CAS  PubMed  Google Scholar 

  • Bhattacharjee A, Richards WG, Staunton J, Li C, Monti S, Vasa P, Ladd C, Beheshti J, Bueno R, Gillette M, Loda M, Weber G, Mark E J, Lander E S, Wong W, Johnson B E, Golub T R, Sugarbaker D J, Meyerson M (2001). Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci USA, 98(24): 13790–13795

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Bjorge J D, Jakymiw A, Fujita D J (2000). Selected glimpses into the activation and function of Src kinase. Oncogene, 19(49): 5620–5635

    Article  CAS  PubMed  Google Scholar 

  • Cance W G, Craven R J, Bergman M, Xu L, Alitalo K, Liu E T (1994). Rak, a novel nuclear tyrosine kinase expressed in epithelial cells. Cell Growth Differ, 5(12): 1347–1355

    CAS  PubMed  Google Scholar 

  • Chan K C, Lio D S, Dobson R C, Jarasrassamee B, Hossain M I, Roslee A K, Ia K K, Perugini M A, Cheng H C (2010). Development of the procedures for high-yield expression and rapid purification of active recombinant Csk-homologous kinase (CHK): comparison of the catalytic activities of CHK and CSK. Protein Expr Purif, 74(2): 139–147

    Article  CAS  PubMed  Google Scholar 

  • Cho J Y, Lim J Y, Cheong J H, Park Y Y, Yoon S L, Kim S M, Kim S B, Kim H, Hong S W, Park Y N, Noh S H, Park E S, Chu I S, Hong W K, Ajani J A, Lee J S (2011). Gene expression signature-based prognostic risk score in gastric cancer, Clin Cancer Res, 17: 1850–1857

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Chong Y P, Chan A S, Chan K C, Williamson N A, Lerner E C, Smithgall T E, Bjorge J D, Fujita D J, Purcell A W, Scholz G, Mulhern T D, Cheng H C (2006). C-terminal Src kinase-homologous kinase (CHK), a unique inhibitor inactivating multiple active conformations of Src family tyrosine kinases. J Biol Chem, 281(44): 32988–32999

    Article  CAS  PubMed  Google Scholar 

  • Chong Y P, Mulhern T D, Cheng H C (2005). C-terminal Src kinase (CSK) and CSK-homologous kinase (CHK)—endogenous negative regulators of Src-family protein kinases. Growth Factors, 23(3): 233–244

    Article  CAS  PubMed  Google Scholar 

  • Chong Y P, Mulhern T D, Zhu H J, Fujita D J, Bjorge J D, Tantiongco J P, Sotirellis N, Lio D S, Scholz G, Cheng H C (2004). A novel noncatalytic mechanism employed by the C-terminal Src-homologous kinase to inhibit Src-family kinase activity. J Biol Chem, 279(20): 20752–20766

    Article  CAS  PubMed  Google Scholar 

  • Chow L M, Davidson D, Fournel M, Gosselin P, Lemieux S, Lyu M S, Kozak C A, Matis L A, Veillette A (1994). Two distinct protein isoforms are encoded by ntk, a csk-related tyrosine protein kinase gene. Oncogene, 9(12): 3437–3448

    CAS  PubMed  Google Scholar 

  • Cordero J B, Ridgway R A, Valeri N, Nixon C, Frame M C, Muller W J, Vidal M, Sansom O J (2014). c-Src drives intestinal regeneration and transformation. EMBO J, 33(13): 1474–1491

    CAS  PubMed Central  PubMed  Google Scholar 

  • Davidson D, Chow L M, Veillette A (1997). Chk, a Csk family tyrosine protein kinase, exhibits Csk-like activity in fibroblasts, but not in an antigen-specific T-cell line. J Biol Chem, 272(2): 1355–1362

    Article  CAS  PubMed  Google Scholar 

  • Han NM, Curley S A, Gallick G E (1996). Differential activation of pp60 (c-src) and pp62(c-yes) in human colorectal carcinoma liver metastases, Clin Cancer Res, 2(8): 1397–1404

    CAS  PubMed  Google Scholar 

  • Hinoue T, Weisenberger D J, Lange C P, Shen H, Byun H M, Van Den Berg D, Malik S, Pan F, Noushmehr H, van Dijk CM, Tollenaar R A, Laird P W (2012). Genome-scale analysis of aberrant DNA methylation in colorectal cancer. Genome Res, 22(2): 271–282

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Hirao A, Huang X L, Suda T, Yamaguchi N (1998). Overexpression of C-terminal Src kinase homologous kinase suppresses activation of Lyn tyrosine kinase required for VLA5-mediated Dami cell spreading. J Biol Chem, 273(16): 10004–10010

    Article  CAS  PubMed  Google Scholar 

  • Huang H, Li L, Wu C, Schibli D, Colwill K, Ma S, Li C, Roy P, Ho K, Songyang Z, Pawson T, Gao Y, Li S S (2008). Defining the specificity space of the human SRC homology 2 domain. Mol Cell Proteomics, 7(4): 768–784

    Article  CAS  PubMed  Google Scholar 

  • Huang K, Wang Y H, Brown A, Sun G (2009). Identification of Nterminal lobe motifs that determine the kinase activity of the catalytic domains and regulatory strategies of Src and Csk protein tyrosine kinases. J Mol Biol, 386(4): 1066–1077

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ia K K, Jeschke G R, Deng Y, Kamaruddin M A, Williamson N A, Scanlon D B, Culvenor J G, Hossain M I, Purcell AW, Liu S, Zhu H J, Catimel B, Turk B E, Cheng H C (2011). Defining the substrate specificity determinants recognized by the active site of C-terminal Src kinase-homologous kinase (CHK) and identification of β-synuclein as a potential CHK physiological substrate. Biochemistry, 50(31): 6667–6677

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ia K K, Mills R D, Hossain M I, Chan K C, Jarasrassamee B, Jorissen R N, Cheng H C (2010). Structural elements and allosteric mechanisms governing regulation and catalysis of CSK-family kinases and their inhibition of Src-family kinases. Growth Factors, 28(5): 329–350

    Article  CAS  PubMed  Google Scholar 

  • Jamros M A, Oliveira L C, Whitford P C, Onuchic J N, Adams J A, Jennings P A (2012). Substrate-specific reorganization of the conformational ensemble of CSK implicates novel modes of kinase function. PLOS Comput Biol, 8(9): e1002695

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kim S O, Avraham S, Jiang S, Zagozdzon R, Fu Y, Avraham H K (2004). Differential expression of Csk homologous kinase (CHK) in normal brain and brain tumors. Cancer, 101(5): 1018–1027

    Article  CAS  PubMed  Google Scholar 

  • Klages S, Adam D, Class K, Fargnoli J, Bolen J B, Penhallow R C (1994). Ctk: a protein-tyrosine kinase related to Csk that defines an enzyme family. Proc Natl Acad Sci USA, 91(7): 2597–2601

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Kuang S Q, Tong W G, Yang H, Lin W, Lee M K, Fang Z H, Wei Y, Jelinek J, Issa J P, Garcia-Manero G (2008). Genome-wide identification of aberrantly methylated promoter associated CpG islands in acute lymphocytic leukemia. Leukemia, 22(8): 1529–1538

    Article  CAS  PubMed  Google Scholar 

  • Kuo S S, Armanini M P, Phillips H S, Caras I W (1997). Csk and BatK show opposite temporal expression in the rat CNS: consistent with its late expression in development, BatK induces differentiation of PC12 cells. Eur J Neurosci, 9(11): 2383–2393

    Article  CAS  PubMed  Google Scholar 

  • Kuo S S, Moran P, Gripp J, Armanini M, Phillips H S, Goddard A, Caras I W (1994). Identification and characterization of Batk, a predominantly brain-specific non-receptor protein tyrosine kinase related to Csk. J Neurosci Res, 38(6): 705–715

    Article  CAS  PubMed  Google Scholar 

  • Laffaire J, Everhard S, Idbaih A, Crinière E, Marie Y, de Reyniès A, Schiappa R, Mokhtari K, Hoang-Xuan K, Sanson M, Delattre J Y, Thillet J, Ducray F (2011). Methylation profiling identifies 2 groups of gliomas according to their tumorigenesis. Neuro-oncol, 13(1): 84–98

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Le X F, Bast R C Jr (2011). Src family kinases and paclitaxel sensitivity. Cancer Biol Ther, 12(4): 260–269

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lee S, Ayrapetov M K, Kemble D J, Parang K, Sun G (2006). Dockingbased substrate recognition by the catalytic domain of a protein tyrosine kinase, C-terminal Src kinase (Csk). J Biol Chem, 281(12): 8183–8189

    Article  CAS  PubMed  Google Scholar 

  • Lerner E C, Smithgall T E (2002). SH3-dependent stimulation of Srcfamily kinase autophosphorylation without tail release from the SH2 domain in vivo. Nat Struct Biol, 9(5): 365–369

    CAS  PubMed  Google Scholar 

  • Lerner E C, Trible R P, Schiavone A P, Hochrein J M, Engen J R, Smithgall T E (2005). Activation of the Src family kinase Hck without SH3-linker release. J Biol Chem, 280(49): 40832–40837

    Article  CAS  PubMed  Google Scholar 

  • Levinson N M, Seeliger M A, Cole P A, Kuriyan J (2008). Structural basis for the recognition of c-Src by its inactivator Csk. Cell, 134(1): 124–134

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Lieser S A, Shaffer J, Adams J A (2006). SRC tail phosphorylation is limited by structural changes in the regulatory tyrosine kinase Csk. J Biol Chem, 281(49): 38004–38012

    Article  CAS  PubMed  Google Scholar 

  • Matsuoka H, Nada S, Okada M (2004). Mechanism of Csk-mediated down-regulation of Src family tyrosine kinases in epidermal growth factor signaling. J Biol Chem, 279(7): 5975–5983

    Article  CAS  PubMed  Google Scholar 

  • Moarefi I, LaFevre-Bernt M, Sicheri F, Huse M, Lee C H, Kuriyan J, Miller W T (1997). Activation of the Src-family tyrosine kinase Hck by SH3 domain displacement. Nature, 385(6617): 650–653

    Article  CAS  PubMed  Google Scholar 

  • Nakayama Y, Kawana A, Igarashi A, Yamaguchi N (2006). Involvement of the N-terminal unique domain of Chk tyrosine kinase in Chkinduced tyrosine phosphorylation in the nucleus. Exp Cell Res, 312(12): 2252–2263

    Article  CAS  PubMed  Google Scholar 

  • Ogawa A, Takayama Y, Sakai H, Chong K T, Takeuchi S, Nakagawa A, Nada S, Okada M, Tsukihara T (2002). Structure of the carboxylterminal Src kinase, Csk. J Biol Chem, 277(17): 14351–14354

    Article  CAS  PubMed  Google Scholar 

  • Okada M (2012). Regulation of the SRC family kinases by Csk. Int J Biol Sci, 8(10): 1385–1397

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Rosenbluh J, Nijhawan D, Cox A G, Li X, Neal J T, Schafer E J, Zack T I, Wang X, Tsherniak A, Schinzel A C, Shao D D, Schumacher S E, Weir B A, Vazquez F, Cowley G S, Root D E, Mesirov J P, Beroukhim R, Kuo C J, Goessling W, Hahn W C (2012). β-Catenindriven cancers require a YAP1 transcriptional complex for survival and tumorigenesis. Cell, 151(7): 1457–1473

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sicheri F, Moarefi I, Kuriyan J (1997). Crystal structure of the Src family tyrosine kinase Hck. Nature, 385(6617): 602–609

    Article  CAS  PubMed  Google Scholar 

  • Sirvent A, Benistant C, Roche S (2012a). Oncogenic signaling by tyrosine kinases of the SRC family in advanced colorectal cancer, Am J Cancer Res, 2(4): 357–371

    CAS  PubMed Central  PubMed  Google Scholar 

  • Sirvent A, Vigy O, Orsetti B, Urbach S, Roche S (2012b). Analysis of SRC oncogenic signaling in colorectal cancer by stable isotope labeling with heavy amino acids in mouse xenografts. Mol Cell Proteomics, 11(12): 1937–1950

    Article  PubMed Central  PubMed  Google Scholar 

  • Summy J M, Gallick G E (2003). Src family kinases in tumor progression and metastasis. Cancer Metastasis Rev, 22(4): 337–358

    Article  CAS  PubMed  Google Scholar 

  • Sun L, Hui A M, Su Q, Vortmeyer A, Kotliarov Y, Pastorino S, Passaniti A, Menon J, Walling J, Bailey R, Rosenblum M, Mikkelsen T, Fine H A (2006). Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain. Cancer Cell, 9(4): 287–300

    Article  CAS  PubMed  Google Scholar 

  • Takeuchi S, Takayama Y, Ogawa A, Tamura K, Okada M (2000). Transmembrane phosphoprotein Cbp positively regulates the activity of the carboxyl-terminal Src kinase, Csk. J Biol Chem, 275(38): 29183–29186

    Article  CAS  PubMed  Google Scholar 

  • Tan S Y, Chuang S S, Tang T, Tan L, Ko Y H, Chuah K L, Ng S B, Chng W J, Gatter K, Loong F, Liu Y H, Hosking P, Cheah P L, Teh B T, Tay K, Koh M, Lim S T (2013). Type II EATL (epitheliotropic intestinal T-cell lymphoma): a neoplasm of intra-epithelial T-cells with predominant CD8αα phenotype. Leukemia, 27(8): 1688–1696

    Article  CAS  PubMed  Google Scholar 

  • Tan S Y, Ooi A S, Ang M K, Koh M, Wong J C, Dykema K, Ngeow J, Loong S, Gatter K, Tan L, Lim L C, Furge K, Tao M, Lim S T, Loong F, Cheah P L, Teh B T (2011). Nuclear expression of MATK is a novel marker of type II enteropathy-associated T-cell lymphoma. Leukemia, 25(3): 555–557

    Article  CAS  PubMed  Google Scholar 

  • Touil Y, Igoudjil W, Corvaisier M, Dessein A F, Vandomme J, Monte D, Stechly L, Skrypek N, Langlois C, Grard G, Millet G, Leteurtre E, Dumont P, Truant S, Pruvot F R, Hebbar M, Fan F, Ellis L M, Formstecher P, van Seuningen I, Gespach C, Polakowska R, Huet G (2014). Colon cancer cells escape 5FU chemotherapy-induced cell death by entering stemness and quiescence associated with the c-Yes/YAP axis, Clin Cancer Res, 20(4): 837–846

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wong L, Lieser S A, Miyashita O, Miller M, Tasken K, Onuchic J N, Adams J A, Woods V L Jr, Jennings P A (2005). Coupled motions in the SH2 and kinase domains of Csk control Src phosphorylation. J Mol Biol, 351(1): 131–143

    Article  CAS  PubMed  Google Scholar 

  • Xu W, Harrison S C, Eck M J (1997). Three-dimensional structure of the tyrosine kinase c-Src. Nature, 385(6617): 595–602

    Article  CAS  PubMed  Google Scholar 

  • Zhu S, Bjorge J D, Cheng H C, Fujita D J (2008). Decreased CHK protein levels are associated with Src activation in colon cancer cells. Oncogene, 27(14): 2027–2034

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, 30 Flemington Road, Parkville, Victoria, 3010, Australia

    Gahana Advani, Ya Chee Lim & Heung-Chin Cheng

  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

    Anderly C. Chueh

  3. Peter MacCallum Cancer Research Institute, St. Andrews Place, East Melbourne, Victoria, Australia

    Amardeep Dhillon

Authors
  1. Gahana Advani
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anderly C. Chueh
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ya Chee Lim
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Amardeep Dhillon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Heung-Chin Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Heung-Chin Cheng.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Advani, G., Chueh, A.C., Lim, Y.C. et al. Csk-homologous kinase (Chk/Matk): a molecular policeman suppressing cancer formation and progression. Front. Biol. 10, 195–202 (2015). https://doi.org/10.1007/s11515-015-1352-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11515-015-1352-4

Keywords

Search

Navigation