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

Advani, Gahana; Chüeh, Anderly C.; Lim, Ya Chee; Dhillon, Amardeep S.; Cheng, Heung‐Chin

doi:10.1007/s11515-015-1352-4

Cited by 4 publications

(6 citation statements)

References 46 publications

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“…However, CHK/MATK overexpression was able to inhibit the doxorubicin‐induced enhancement of cell migration. Previous research shows in normal untreated cells, SFKs remain in the stable inactive conformation until activated in some cellular events, including doxorubicin treatment and cell migration 17,23 . We then activated the Src system through sublethal concentrations of doxorubicin, as shown in our earlier experiments, and therefore, examined Src phosphorylation at Tyr‐416 and Tyr‐527 in our U2OS WT cells overexpressing CHK/MATK cells.…”

Section: Discussionmentioning

confidence: 94%

“…Previous research shows in normal untreated cells, SFKs remain in the stable inactive conformation until activated in some cellular events, including doxorubicin treatment and cell migration. 17 , 23 We then activated the Src system through sublethal concentrations of doxorubicin, as shown in our earlier experiments, and therefore, examined Src phosphorylation at Tyr‐416 and Tyr‐527 in our U2OS WT cells overexpressing CHK/MATK cells. In parallel with our data showing that CHK/MATK overexpression inhibited doxorubicin‐induced cell migration, there was no effect on Src activation/phosphorylation when these cells were treated with sublethal concentration of doxorubicin.…”

Section: Discussionmentioning

confidence: 99%

“…While Csk is ubiquitously expressed in mammalian cells, CHK/MATK is predominantly found in hematopoietic cells and neurons 14–16 . Csk and CHK/MATK share a similar structural composition with Src, possessing a SH2, SH3 and kinase domain; however, they lack the C‐terminal tail phosphorylation site and N‐terminal myristoyl group, 14 despite their structural resemblance, the binding domains of Csk and CHK/MATK exhibit differences, as their SH2 domains engage with distinct phosphoproteins and target Csk and CHK/MATK to various cellular compartments 17 . Both inhibitors were previously reported to catalyze the phosphorylation of the C‐terminal tail tyrosine of Src at Tyr‐527, but recent studies have shown CHK/MATK to be ineffective at phosphorylating Src C‐terminal regulatory Tyr‐527 13 .…”

Section: Introductionmentioning

confidence: 99%

“… 14 , 15 , 16 Csk and CHK/MATK share a similar structural composition with Src, possessing a SH2, SH3 and kinase domain; however, they lack the C‐terminal tail phosphorylation site and N‐terminal myristoyl group, 14 despite their structural resemblance, the binding domains of Csk and CHK/MATK exhibit differences, as their SH2 domains engage with distinct phosphoproteins and target Csk and CHK/MATK to various cellular compartments. 17 Both inhibitors were previously reported to catalyze the phosphorylation of the C‐terminal tail tyrosine of Src at Tyr‐527, but recent studies have shown CHK/MATK to be ineffective at phosphorylating Src C‐terminal regulatory Tyr‐527. 13 Unlike Csk, CHK/MATK has also been shown to directly bind to Src via a non‐catalytic mechanism, thereby preventing autophosphorylation at Tyr‐416 and inhibiting Src activation without affecting Tyr‐527 phosphorylation, and subsequently, inhibit cellular processes such as cell migration.…”

Section: Introductionmentioning

confidence: 99%

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MMP‐2 regulates Src activation via repression of the CHK/MATK tumor suppressor in osteosarcoma

Maybee,

Cromwell,

Hubbard

et al. 2023

Cancer Reports

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BackgroundDoxorubicin, a first‐line anticancer drug for osteosarcoma treatment, has been the subject of recent research exploring the mechanisms behind its chemoresistance and its ability to enhance cell migration at sublethal concentrations. Matrix metalloproteinase‐2 (MMP‐2), a type IV collagenase and zinc‐dependent endopeptidase, is well‐known for degrading the extracellular matrix and promoting cancer metastasis. Our previous work demonstrated that nuclear MMP‐2 regulates ribosomal RNA transcription via histone clipping, thereby controlling gene expression. Additionally, MMP‐2 activity is regulated by the non‐receptor tyrosine kinase and oncogene, Src, which plays a crucial role in cell adhesion, invasion, and metastasis. Src kinase is primarily regulated by two endogenous inhibitors: C‐terminal Src kinase (Csk) and Csk homologous kinase (CHK/MATK).AimIn this study, we reveal that the MMP‐2 gene acts as an upstream regulator of Src kinase activity by suppressing its endogenous inhibitor, CHK/MATK, in osteosarcoma cells.Methods and ResultsWe show that enhanced osteosarcoma cell migration which is induced by sublethal concentrations of doxorubicin can be overcome by inactivating the MMP‐2 gene or overexpressing CHK/MATK. Our findings highlight the MMP‐2 gene as a promising additional target for combating cancer cell migration and metastasis. This is due to its role in suppressing on the gene and protein expression of the tumor suppressor CHK/MATK in osteosarcoma.ConclusionBy targeting the MMP‐2 gene, we can potentially enhance the effectiveness of doxorubicin treatment and reduce chemoresistance in osteosarcoma.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

MMP‐2 regulates Src activation via repression of the CHK/MATK tumor suppressor in osteosarcoma

Maybee,

Cromwell,

Hubbard

et al. 2023

Cancer Reports

View full text Add to dashboard Cite

show abstract

“…Csk and CHK/MATK share a similar structural composition with Src, possessing a SH2, SH3 and kinase domain; however, they lack the C-terminal tail phosphorylation site and N-terminal myristoyl group (14). Despite their structural resemblance, the binding domains of Csk and CHK/MATK exhibit differences, as their SH2 domains engage with distinct phosphoproteins and target Csk and CHK/MATK to various cellular compartments (17). Both inhibitors were previously reported to catalyze the phosphorylation of the C-terminal tail tyrosine of Src at Tyr-527, but recent studies have shown CHK/MATK to be ineffective at phosphorylating Src C-terminal regulatory Tyr-527 (13).…”

Section: Introductionmentioning

confidence: 99%

MMP-2 regulates Src activation via repression of the CHK/MATK tumor suppressor in Osteosarcoma

Maybee

Cromwell

Hubbard

et al. 2023

Preprint

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Doxorubicin, a first-line anticancer drug for osteosarcoma treatment, has been the subject of recent research exploring the mechanisms behind its chemoresistance and its ability to enhance cell migration at sublethal concentrations. Matrix metalloproteinase-2 (MMP-2), a type IV collagenase and zinc-dependent endopeptidase, is well-known for degrading the extracellular matrix and promoting cancer metastasis. Our previous work demonstrated that nuclear MMP-2 regulates ribosomal RNA transcription via histone clipping, thereby controlling gene expression. Additionally, MMP-2 activity is regulated by the non-receptor tyrosine kinase and oncogene, Src, which plays a crucial role in cell adhesion, invasion, and metastasis. Src kinase is primarily regulated by two endogenous inhibitors: C-terminal Src kinase (Csk) and Csk homologous kinase (CHK/MATK). In this study, we reveal that the MMP-2 gene acts as an upstream regulator of Src kinase activity by suppressing its endogenous inhibitor, CHK/MATK, in osteosarcoma cells. We also show that enhanced osteosarcoma cell migration which is induced by sublethal concentrations of doxorubicin can be overcome by inactivating the MMP-2 gene or overexpressing CHK/MATK. Our findings highlight the MMP-2 gene as a promising additional target for combating cancer cell migration and metastasis. This is due to its impact on the gene and protein expression of the tumor suppressor CHK/MATK in osteosarcoma. By targeting the MMP-2 gene, we can potentially enhance the effectiveness of doxorubicin treatment and reduce chemoresistance in osteosarcoma.

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