Csk-homologous kinase (Chk) is an efficient inhibitor of Src-family kinases but a poor catalyst of phosphorylation of their C-terminal regulatory tyrosine

Advani, Gahana; Lim, Ya Chee; Catimel, Bruno; Lio, Daisy Sio Seng; Ng, Nadia L.Y.; Chüeh, Anderly C.; Tran, Mai X.; Anasir, Mohd Ishtiaq; Verkade, Heather; Zhu, Hong; Turk, Benjamin E.; Smithgall, Thomas E.; C, Ang; Griffin, Michael D. W.; Cheng, Heung‐Chin

doi:10.1186/s12964-017-0186-x

Cited by 13 publications

(18 citation statements)

References 79 publications

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“…Chk can engage a complementary mechanism to inhibit SFKs by direct binding to SFKs, which is also called as non-catalytic inhibitory mechanism. Several other signaling proteins such as paxillin, P2X3 receptor, c-Jun and Lats can also serves as substrates of Csk, but the physiological relevance of it is not yet known [ 151 , 170 ].…”

Section: Non Receptor Tyrosine Kinase Familiesmentioning

confidence: 99%

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Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products

et al. 2018

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Tyrosine kinases belong to a family of enzymes that mediate the movement of the phosphate group to tyrosine residues of target protein, thus transmitting signals from the cell surface to cytoplasmic proteins and the nucleus to regulate physiological processes. Non-receptor tyrosine kinases (NRTK) are a sub-group of tyrosine kinases, which can relay intracellular signals originating from extracellular receptor. NRTKs can regulate a huge array of cellular functions such as cell survival, division/propagation and adhesion, gene expression, immune response, etc. NRTKs exhibit considerable variability in their structural make up, having a shared kinase domain and commonly possessing many other domains such as SH2, SH3 which are protein-protein interacting domains. Recent studies show that NRTKs are mutated in several hematological malignancies, including lymphomas, leukemias and myelomas, leading to aberrant activation. It can be due to point mutations which are intragenic changes or by fusion of genes leading to chromosome translocation. Mutations that lead to constitutive kinase activity result in the formation of oncogenes, such as Abl, Fes, Src, etc. Therefore, specific kinase inhibitors have been sought after to target mutated kinases. A number of compounds have since been discovered, which have shown to inhibit the activity of NRTKs, which are remarkably well tolerated. This review covers the role of various NRTKs in the development of hematological cancers, including their deregulation, genetic alterations, aberrant activation and associated mutations. In addition, it also looks at the recent advances in the development of novel natural compounds that can target NRTKs and perhaps in combination with other forms of therapy can show great promise for the treatment of hematological malignancies.

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Section: Non Receptor Tyrosine Kinase Familiesmentioning

confidence: 99%

“…Csk is ubiquitously expressed in all cells, however, Chk is mainly expressed in the brain, haematopoietic cells, colon tissue and smooth muscle cells [ 170 ]. Csk is primarily present in cytosol as it does not have a transmembrane domain or any fatty acyl modifications.…”

Section: Non Receptor Tyrosine Kinase Familiesmentioning

confidence: 99%

Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products

et al. 2018

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“…When expressed in CSK deficient fibroblasts of mouse embryo, CHK downregulates Src kinase activity (Davidson et al, 1997). Moreover, CHK is able to phosphorylate Src at its C-terminal in vitro, accompanied by Src inactivation (Advani et al, 2017). These lines of evidence indicate Src is a physiological phosphorylation substrate of CHK kinase.…”

Section: Subcellular Localization and Cellular Roles Of Chkmentioning

confidence: 96%

“…The basic residues including Arg276, Arg278, and Arg280 (in αD helix) and Arg382 and Lys387 (in αF-αG loop) are important for the catalytic activity of CHK. Among these residues, Arg382 and Lys387 have mild effects on the affinity of CHK for SFKs (Advani et al, 2017).…”

Section: Structure and Isoforms Of Chkmentioning

confidence: 99%

Regulation, targets and functions of CHK

Zhu

Sun

Guo³

et al. 2022

Front. Cell Dev. Biol.

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Src family kinases (SFKs) play pivotal roles in multiple signaling pathways (Yeatman, 2004). SFK activity is inhibited by phosphorylation at its C-terminal tyrosine, by CSK (C-terminal Src kinase) and CHK (CSK-homologous kinase). CHK expression is restricted to normal hematopoietic cells, brain, and colon tissues. Downregulation of CHK in brain and colon tumors contributes to tumorigenicity in these tissues. CHK does not phosphorylate Src efficiently, however, in contrast to CSK, CHK inhibits Src kinase activity allosterically. Although the functions of CHK are still largely unknown, potential substrates of CHK including β-synuclein, α-tubulin, α-spectrin, 14-3-3, and Hsp90 have been identified. CHK is regulated epigenetically via promoter methylation. As the unknown roles of CHK are beginning to be revealed, current knowledge of regulation, molecular targets and functions of CHK is summarized, and important topics for future CHK research are discussed.

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“…CHK has been reported to be expressed primarily in brain and hematopoietic cells ( Chow et al, 1994 ). Unlike Csk, which phosphorylates and inhibits Src effectively, CHK is not capable of phosphorylating Src Y530 effectively ( Advani et al, 2017 ). The molecular and functional roles of CHK are largely uncharacterized.…”

Section: Introductionmentioning

confidence: 99%

CHK Methylation Is Elevated in Colon Cancer Cells and Contributes to the Oncogenic Properties

Zhu

Wang

et al. 2021

Front. Cell Dev. Biol.

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Src is an important oncogene that plays key roles in multiple signal transduction pathways. Csk-homologous kinase (CHK) is a kinase whose molecular roles are largely uncharacterized. We previously reported expression of CHK in normal human colon cells, and decreased levels of CHK protein in colon cancer cells leads to the activation of Src (Zhu et al., 2008). However, how CHK protein expression is downregulated in colon cancer cells has been unknown. We report herein that CHK mRNA was decreased in colon cancer cells as compared to normal colon cells, and similarly in human tissues of normal colon and colon cancer. Increased levels of DNA methylation at promotor CpG islands of CHK gene were observed in colon cancer cells and human colon cancer tissues as compared to their normal healthy counterparts. Increased levels of DNA methyltransferases (DNMTs) were also observed in colon cancer cells and tissues. DNA methylation and decreased expression of CHK mRNA were inhibited by DNMT inhibitor 5-Aza-CdR. Cell proliferation, colony growth, wound healing, and Matrigel invasion were all decreased in the presence of 5-Aza-CdR. These results suggest that increased levels of DNA methylation, possibly induced by enhanced levels of DNMT, leads to decreased expression of CHK mRNA and CHK protein, promoting increased oncogenic properties in colon cancer cells.

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Csk-homologous kinase (Chk) is an efficient inhibitor of Src-family kinases but a poor catalyst of phosphorylation of their C-terminal regulatory tyrosine

Cited by 13 publications

References 79 publications

Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products

Role of Non Receptor Tyrosine Kinases in Hematological Malignances and its Targeting by Natural Products

Regulation, targets and functions of CHK

CHK Methylation Is Elevated in Colon Cancer Cells and Contributes to the Oncogenic Properties

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