The end of mitosis from a phosphatase perspective

Visconti, Roberta; Palazzo, Luca; Pepe, Anna; Monica, Rosa Della; Grieco, Domenico

doi:10.4161/cc.22875

Cited by 9 publications

(11 citation statements)

References 34 publications

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“…In preliminary experiments, in which Fcp1 expression was downregulated in HeLa cells by small interfering RNAs (siRNAs), we found that dephosphorylations of bulk K/HpSP motif and pT481-PRC1 at mitosis exit were indeed dependent on Fcp1 ( Figure 1—figure supplement 1 ). However, given the role for Fcp1 in inactivation of the spindle assembly checkpoint and of Cdk1 ( Visconti et al, 2012 ; Visconti et al, 2013 ), delayed dephosphorylations could be due to persistance of Cdk1 kinase activity rather than impaired PP2A-B55 phosphatase activation at the end of mitosis. To know whether Fcp1 controlled PP2A-B55 activation downstream Cdk1 inactivation, we determined whether Fcp1 depletion impaired bulk K/HpSP motif and pT481-PRC1 dephosphorylation upon chemical inhibition of Cdk1 activity in mitotic cells and cell extracts.…”

Section: Resultsmentioning

confidence: 99%

Fcp1 phosphatase controls Greatwall kinase to promote PP2A-B55 activation and mitotic progression

Monica

Visconti

Cervone

et al. 2015

eLife

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During cell division, progression through mitosis is driven by a protein phosphorylation wave. This wave namely depends on an activation-inactivation cycle of cyclin B-dependent kinase (Cdk) 1 while activities of major protein phosphatases, like PP1 and PP2A, appear directly or indirectly repressed by Cdk1. However, how Cdk1 inactivation is coordinated with reactivation of major phosphatases at mitosis exit still lacks substantial knowledge. We show here that activation of PP2A-B55, a major mitosis exit phosphatase, required the phosphatase Fcp1 downstream Cdk1 inactivation in human cells. During mitosis exit, Fcp1 bound Greatwall (Gwl), a Cdk1-stimulated kinase that phosphorylates Ensa/ARPP19 and converts these proteins into potent PP2A-B55 inhibitors during mitosis onset, and dephosphorylated it at Cdk1 phosphorylation sites. Fcp1-catalyzed dephosphorylation drastically reduced Gwl kinase activity towards Ensa/ARPP19 promoting PP2A-B55 activation. Thus, Fcp1 coordinates Cdk1 and Gwl inactivation to derepress PP2A-B55, generating a dephosphorylation switch that drives mitosis progression.DOI: http://dx.doi.org/10.7554/eLife.10399.001

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Section: Resultsmentioning

confidence: 99%

Fcp1 phosphatase controls Greatwall kinase to promote PP2A-B55 activation and mitotic progression

Monica

Visconti

Cervone

et al. 2015

eLife

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“… 1 , 8 , 9 By studying mitosis exit and SAC resolution, we recently reported a role for the Fcp1 phosphatase to bring about cdk1 inactivation. 10 , 11 Among Fcp1 targets, we identified cyclin degradation pathway components, such as Cdc20, an APC/C co-activator, USP44, a deubiquitinating enzyme, and Wee1. 10 , 11 Wee1 is a crucial kinase that controls the G2 phase by performing inhibitory phosphorylation of cdk1 at tyr-15 (Y15-cdk1).…”

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confidence: 99%

“… 10 , 11 Among Fcp1 targets, we identified cyclin degradation pathway components, such as Cdc20, an APC/C co-activator, USP44, a deubiquitinating enzyme, and Wee1. 10 , 11 Wee1 is a crucial kinase that controls the G2 phase by performing inhibitory phosphorylation of cdk1 at tyr-15 (Y15-cdk1). Wee1 is also in a feedback relationship with cdk1 itself that, in turn, can phosphorylate and inhibit Wee1 in an autoamplification loop to promote the G2-to-M phase transition.…”

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The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs

et al. 2015

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To grant faithful chromosome segregation, the spindle assembly checkpoint (SAC) delays mitosis exit until mitotic spindle assembly. An exceedingly prolonged mitosis, however, promotes cell death and by this means antimicrotubule cancer drugs (AMCDs), that impair spindle assembly, are believed to kill cancer cells. Despite malformed spindles, cancer cells can, however, slip through SAC, exit mitosis prematurely and resist killing. We show here that the Fcp1 phosphatase and Wee1, the cyclin B-dependent kinase (cdk) 1 inhibitory kinase, play a role for this slippage/resistance mechanism. During AMCD-induced prolonged mitosis, Fcp1-dependent Wee1 reactivation lowered cdk1 activity, weakening SAC-dependent mitotic arrest and leading to mitosis exit and survival. Conversely, genetic or chemical Wee1 inhibition strengthened the SAC, further extended mitosis, reduced antiapoptotic protein Mcl-1 to a minimum and potentiated killing in several, AMCD-treated cancer cell lines and primary human adult lymphoblastic leukemia cells. Thus, the Fcp1-Wee1-Cdk1 (FWC) axis affects SAC robustness and AMCDs sensitivity.

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“…3, we have proved that WEE1 also contributes to the control of mitosis exit. Indeed, CDK1 undergoes transient WEE1-dependent tyr-15 phosphorylation at the end of mitosis (D'Angiolella et al 2007, Visconti et al 2012, and this is dependent on the phosphatase FCP1 that dephosphorylates and activates the WEE1 kinase activity at mitosis exit (Visconti et al 2012(Visconti et al , 2013. More recently, we found that the FCP1-WEE1 pathway also has a crucial role in the mechanisms by which cells adapt to the SAC.…”

Section: :9mentioning

confidence: 85%

Fighting tubulin-targeting anticancer drug toxicity and resistance

Visconti

Grieco

2017

Endocrine-Related Cancer

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Tubulin-targeting drugs, like taxanes and vinca alkaloids, are among the most effective anticancer therapeutics used in the clinic today. Specifically, anti-microtubule cancer drugs (AMCDs) have proven to be effective in the treatment of castration-resistant prostate cancer and triple-negative breast cancer. AMCDs, however, have limiting toxicities that include neutropenia and neurotoxicity, and, in addition, tumor cells can become resistant to the drugs after long-term use. Co-targeting mitotic progression/ slippage with inhibition of the protein kinases WEE1 and MYT1 that regulate CDK1 kinase activity may improve AMCD efficacy, reducing the acquisition of resistance by the tumor and side effects from the drug and/or its vehicle. Other possible treatments that improve outcomes in the clinic for these two drug-resistant cancers, including new formulations of the AMCDs and pursuing different molecular targets, will be discussed.

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The end of mitosis from a phosphatase perspective

Cited by 9 publications

References 34 publications

Fcp1 phosphatase controls Greatwall kinase to promote PP2A-B55 activation and mitotic progression

Fcp1 phosphatase controls Greatwall kinase to promote PP2A-B55 activation and mitotic progression

The Fcp1-Wee1-Cdk1 axis affects spindle assembly checkpoint robustness and sensitivity to antimicrotubule cancer drugs

Fighting tubulin-targeting anticancer drug toxicity and resistance

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