The tyrosine kinase v-Src causes mitotic slippage by phosphorylating an inhibitory tyrosine residue of Cdk1

Horiuchi, Maria; Kuga, Tetsurō; Saito, Youhei; Nagano, Maiko; Adachi, Jun; Tomonaga, Takeshi; Yamaguchi, Naoto; Nakayama, Yuji

doi:10.1074/jbc.ra118.002784

Cited by 23 publications

(38 citation statements)

References 54 publications

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“…Mechanistically, Src can promote delocalization of cytokinesis regulators including Aurora B and kinesin-like protein KIF23 and maintain YAP nuclear activity to weaken the tetraploidy checkpoint [ 103 ]. Src can induce mitotic slippage resulting in aneuploidy and therapeutic cell resistance by direct inhibition of the mitotic regulator Cyclin-Dependent Kinase 1 [ 104 ]. These Src mitotic defects may also contribute to CRC cell invasive behaviour.…”

Section: Sfks In Human Crcmentioning

confidence: 99%

Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis

Sirvent

Mevizou

Naim

et al. 2020

Cancers

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Src, originally identified as an oncogene, is a membrane-anchored tyrosine kinase and the Src family kinase (SFK) prototype. SFKs regulate the signalling induced by a wide range of cell surface receptors leading to epithelial cell growth and adhesion. In the intestine, the SFK members Src, Fyn and Yes regulate epithelial cell proliferation and migration during tissue regeneration and transformation, thus implicating conserved and specific functions. In patients with colon cancer, SFK activity is a marker of poor clinical prognosis and a potent driver of metastasis formation. These tumorigenic activities are linked to SFK capacity to promote the dissemination and tumour-initiating capacities of epithelial tumour cells. However, it is unclear how SFKs promote colon tumour formation and metastatic progression because SFK-encoding genes are unfrequently mutated in human cancer. Here, we review recent findings on SFK signalling during intestinal homeostasis, regeneration and tumorigenesis. We also describe the key nongenetic mechanisms underlying SFK tumour activities in colorectal cancer, and discuss how these mechanisms could be exploited in therapeutic strategies to target SFK signalling in metastatic colon cancer.

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Section: Sfks In Human Crcmentioning

confidence: 99%

Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis

Sirvent

Mevizou

Naim

et al. 2020

Cancers

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“…Under normal conditions, if the cell damage cannot be repaired, then the cells are unable to undergo mitosis, thereby initiating the apoptotic pathway and inducing apoptosis to achieve the ultimate goal of tumor cell death (21)(22)(23)(24). However, certain cells ignore the spindle structure that is formed during mitosis, and in the case of functional disruption, the nucleus does not divide prior to entering the next cell cycle, forming polyploid tumor cells, which enhances resistance to chemotherapeutic drugs (25)(26)(27).…”

Section: Discussionmentioning

confidence: 99%

Role of Bcl‑2 on drug resistance in breast cancer polyploidy‑induced spindle poisons

et al. 2020

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Spindle poisons are chemotherapeutic drugs used in the treatment of malignant tumors; however, numerous patients develop resistance following chemotherapy. The present study aimed to induce polyploidy in breast cancer cells using the spindle poison nocodazole to investigate the mechanism of polyploid-induced tumor resistance. It was revealed that the spindle poison nocodazole induced apoptosis in HCC1806 cells but also induced polyploidy in MDA-MB-231 cells. The drug sensitivities of the polyploid MDA-MB-231 cells to paclitaxel, docetaxel, epirubicin, 5-fluorouracil and oxaliplatin were lower than those of the original tumor cells; however, the polyploid MDA-MB-231 cells were more sensitive to etoposide than the original tumor cells. The expression of F-box and WD repeat domain containing 7 (FBW7) was decreased, while the expression of MCL1 apoptosis regulator BCL2 family member (MCL-1) and Bcl-2 was increased, and caspase-3/9 and Bax were not expressed in MDA-MB-231 cells. The resistance to docetaxel and etoposide was reversed, but the sensitivity of paclitaxel was not changed following Bcl-2 silencing. The formation of polyploidy in tumors may be one of the molecular mechanisms underlying tumor resistance to spindle poisons. Expression of the Bcl-2 family members, for example FBW7 and MCL-1, plays a key role in apoptosis and the cell escape process that forms polyploid cells. However, Bcl-2 silencing has different reversal effects on different anti-tumor drugs, which requires further investigation.

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“…Immunofluorescence staining was performed, as described previously [42,43]. In brief, cells were fixed with 4% formaldehyde in phosphate-buffered saline (PBS) at room temperature for 20 min.…”

Section: Immunofluorescence Microscopymentioning

confidence: 99%

Targeting Insulin-Like Growth Factor 1 Receptor Delays M-Phase Progression and Synergizes with Aurora B Inhibition to Suppress Cell Proliferation

Yamagishi

Ikeda

Ikeuchi

et al. 2020

IJMS

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The insulin-like growth factor 1 receptor (IGF1R) is a receptor-type tyrosine kinase that transduces signals related to cell proliferation, differentiation, and survival. IGF1R expression is often misregulated in tumor cells, but the relevance of this for cancer progression remains unclear. Here, we examined the impact of IGF1R inhibition on cell division. We found that siRNA-mediated knockdown of IGF1R from HeLa S3 cells leads to M-phase delays. Although IGF1R depletion causes partial exclusion of FoxM1 from the nucleus, quantitative real-time PCR revealed that the transcription of M-phase regulators is not affected by decreased levels of IGF1R. Moreover, a similar delay in M phase was observed following 2 h of incubation with the IGF1R inhibitors OSI-906 and NVP-ADW742. These results suggest that the M-phase delay observed in IGF1R-compromised cells is not caused by altered expression of mitotic regulators. Live-cell imaging revealed that both prolonged prometaphase and prolonged metaphase underlie the delay and this can be abrogated by the inhibition of Mps1 with AZ3146, suggesting activation of the Spindle Assembly Checkpoint when IGF1R is inhibited. Furthermore, incubation with the Aurora B inhibitor ZM447439 potentiated the IGF1R inhibitor-induced suppression of cell proliferation, opening up new possibilities for more effective cancer chemotherapy.

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The tyrosine kinase v-Src causes mitotic slippage by phosphorylating an inhibitory tyrosine residue of Cdk1

Cited by 23 publications

References 54 publications

Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis

Src Family Tyrosine Kinases in Intestinal Homeostasis, Regeneration and Tumorigenesis

Role of Bcl‑2 on drug resistance in breast cancer polyploidy‑induced spindle poisons

Targeting Insulin-Like Growth Factor 1 Receptor Delays M-Phase Progression and Synergizes with Aurora B Inhibition to Suppress Cell Proliferation

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