Fyn Accelerates M Phase Progression by Promoting the Assembly of Mitotic Spindle Microtubules

Okamoto, Mai; Nakayama, Yuji; Kakihana, Ayana; Yuki, Ryuzaburo; Yamaguchi, Noritaka; Yamaguchi, Naoto

doi:10.1002/jcb.25373

Cited by 17 publications

(19 citation statements)

References 58 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Triple knockout mutations of c-Src, c-Yes, and Fyn in SYF cells (18) resulted in spindle misorientation, and re-introduction of c-Src rescued it (19). Re-introduction of Fyn into SYF cells facilitates mitotic spindle formation by increasing microtubule polymerization, leading to the acceleration of M-phase progression (20). Based on the role of the Src-family kinases in cell division and the requirement of spatio-temporal regulation of mitotic kinases, we expected that v-Src could disturb cell division because its kinase activity and subcellular localization are deregulated and different from those of c-Src (6).…”

mentioning

confidence: 99%

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

Horiuchi

Kuga

Saito

et al. 2018

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

The nonreceptor tyrosine kinase v-Src is an oncogene first identified in Rous sarcoma virus. The oncogenic effects of v-Src have been intensively studied; however, its effects on chromosomal integrity are not fully understood. Here, using HeLa S3/v-Src cells having inducible v-Src expression, we found that v-Src causes mitotic slippage in addition to cytokinesis failure, even when the spindle assembly checkpoint is not satisfied because of the presence of microtubule-targeting agents. v-Src's effect on mitotic slippage was also observed in cells after a knockdown of C-terminal Src kinase (Csk), a protein-tyrosine kinase that inhibits Src-family kinases and was partially inhibited by PP2, an Src-family kinase inhibitor. Proteomic analysis and kinase assay revealed that v-Src phosphorylates cyclin-dependent kinase 1 (Cdk1) at Tyr-15. This phosphorylation attenuated Cdk1 kinase activity, resulting in a decrease in the phosphorylation of Cdk1 substrates. Furthermore, v-Src-induced mitotic slippage reduced the sensitivity of the cells to microtubule-targeting agents, and cells that survived the microtubule-targeting agents exhibited polyploidy. These results suggest that v-Src causes mitotic slippage by attenuating Cdk1 kinase activity via direct phosphorylation of Cdk1 at Tyr-15. On the basis of these findings, we propose a model for v-Src-induced oncogenesis, in which v-Src-promoted mitotic slippage due to Cdk1 phosphorylation generates genetic diversity via abnormal cell division of polyploid cells and also increases the tolerance of cancer cells to microtubule-targeting agents.

show abstract

mentioning

confidence: 99%

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

Horiuchi

Kuga

Saito

et al. 2018

Journal of Biological Chemistry

Self Cite

View full text Add to dashboard Cite

show abstract

“…We have shown that Src-family tyrosine kinases play important roles in mitosis141826272832. In particular, mitotic activation of c-Src, c-Yes, Lyn and Fyn, which are all co-expressed in HeLa cells, takes place downstream of Cdk1 activation during M phase18.…”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, Src-family kinases have been reported to regulate cell division232425. We then found the roles of Src-family kinases in spindle orientation, spindle assembly, and cytokinesis abscission17262728. Despite the importance of membrane anchorage of Src-family kinases, the role for their lipid modifications in cell division is largely unknown.…”

mentioning

confidence: 96%

Protective role for lipid modifications of Src-family kinases against chromosome missegregation

Honda

Soeda

Tsuda

et al. 2016

Sci Rep

Self Cite

View full text Add to dashboard Cite

Src-family tyrosine kinases, which are expressed in various cell types, play critical roles in cell signalling at the cytoplasmic side of the plasma membrane through their lipid modifications. Src-family kinases are cotranslationally myristoylated and posttranslationally palmitoylated in the amino-terminal region. The Src-family member Lyn contains a myristoylation site at glycine-2 and a palmitoylation site at cysteine-3, whereas c-Src has a myristoylation site at glycine-2 but not any palmitoylation sites. However, little is known about the role for lipid modifications of Src-family kinases in cell division. Here, we show that non-lipid-modified Lyn and c-Src, Lyn(G2A/C3A) and c-Src(G2A), are delocalized from membranes to the cytoplasm and the nucleus, which gives rise to a significant increase in the rate of chromosome missegregation, such as chromosome lagging and anaphase chromosome bridging, in a tyrosine kinase activity-dependent manner. Treatment with the Src inhibitor PP2 shows that the kinase activity of non-lipid-modified, non-membrane-bound Src during M phase is critical for giving rise to chromosome missegregation. Given that only a fraction of Src-family kinases fails in lipid modifications during biosynthesis, these results suggest that Src’s membrane anchorage through their lipid modifications from prophase to anaphase plays a protective role against induction of chromosome missegregation.

show abstract

“…Each member of the Src family kinases appears to have a distinct role in cell division. Fyn, a member of Src family kinases, participates in the assembly of mitotic spindle microtubules and accelerates mitotic progression [36]. c-Src promotes proper spindle orientation in early prometaphase [37].…”

Section: V-src Suppresses Cell Proliferation and Induces Tetraploimentioning

confidence: 99%

Cytokinesis Failure Leading to Chromosome Instability in v-Src-Induced Oncogenesis

Nakayama

Soeda

Ikeuchi

et al. 2017

IJMS

Self Cite

View full text Add to dashboard Cite

v-Src, an oncogene found in Rous sarcoma virus, is a constitutively active variant of c-Src. Activation of Src is observed frequently in colorectal and breast cancers, and is critical in tumor progression through multiple processes. However, in some experimental conditions, v-Src causes growth suppression and apoptosis. In this review, we highlight recent progress in our understanding of cytokinesis failure and the attenuation of the tetraploidy checkpoint in v-Src-expressing cells. v-Src induces cell cycle changes—such as the accumulation of the 4N cell population—and increases the number of binucleated cells, which is accompanied by an excess number of centrosomes. Time-lapse analysis of v-Src-expressing cells showed that cytokinesis failure is caused by cleavage furrow regression. Microscopic analysis revealed that v-Src induces delocalization of cytokinesis regulators including Aurora B and Mklp1. Tetraploid cell formation is one of the causes of chromosome instability; however, tetraploid cells can be eliminated at the tetraploidy checkpoint. Interestingly, v-Src weakens the tetraploidy checkpoint by inhibiting the nuclear exclusion of the transcription coactivator YAP, which is downstream of the Hippo pathway and its nuclear exclusion is critical in the tetraploidy checkpoint. We also discuss the relationship between v-Src-induced chromosome instability and growth suppression in v-Src-induced oncogenesis.

show abstract

Fyn Accelerates M Phase Progression by Promoting the Assembly of Mitotic Spindle Microtubules

Cited by 17 publications

References 58 publications

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

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

Protective role for lipid modifications of Src-family kinases against chromosome missegregation

Cytokinesis Failure Leading to Chromosome Instability in v-Src-Induced Oncogenesis

Contact Info

Product

Resources

About