Human Cdc14A regulates Wee1 stability by counteracting CDK-mediated phosphorylation

Ovejero, Sara; Ayala, Patricia; Bueno, Avelino; Sacristán, María P.

doi:10.1091/mbc.e12-04-0260

Cited by 31 publications

(59 citation statements)

References 43 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous studies have shown that for cells to activate CDK2, CDK2 protein has to bind to its regulatory subunit cyclin E or A, the Thr160 site has to be phosphorylated by CDK activator (CAK), and CDC25 has to dephosphorylate its Thr14 and Tyr15 sites 14, 15. Our data showed that the phosphorylation levels of CDK2 Thr160 and Thr14/Tyr15 were not affected by DOC-1R overexpression (Fig.…”

Section: Resultssupporting

confidence: 49%

Overexpression of DOC-1R Inhibits Cell Cycle G1/S Transition by Repressing CDK2 Expression and Activation

Liu¹,

Liu²,

Gao³

et al. 2013

Int. J. Biol. Sci.

View full text Add to dashboard Cite

DOC-1R (deleted in oral cancer-1 related) is a novel putative tumor suppressor. This study investigated DOC-1R antitumor activity and the underlying molecular mechanisms. Cell phenotypes were assessed using flow cytometry, BrdU incorporation and CDK2 kinase assays in DOC-1R overexpressing HeLa cells. In addition, RT-PCR and Western blot assays were used to detect underlying molecular changes in these cells. The interaction between DOC-1R and CDK2 proteins was assayed by GST pull-down and immunoprecipitation-Western blot assays. The data showed that DOC-1R overexpression inhibited G1/S phase transition, DNA replication and suppressed CDK2 activity. Molecularly, DOC-1R inhibited CDK2 expression at the mRNA and protein levels, and there were decreased levels of G1-phase cyclins (cyclin D1 and E) and elevated levels of p21, p27, and p53 proteins. Meanwhile, DOC-1R associated with CDK2 and inhibited CDK2 activation by obstructing its association with cyclin E and A. In conclusion, the antitumor effects of DOC-1R may be mediated by negatively regulating G1 phase progression and G1/S transition through inhibiting CDK2 expression and activation.

show abstract

Section: Resultssupporting

confidence: 49%

Overexpression of DOC-1R Inhibits Cell Cycle G1/S Transition by Repressing CDK2 Expression and Activation

Liu¹,

Liu²,

Gao³

et al. 2013

Int. J. Biol. Sci.

View full text Add to dashboard Cite

show abstract

“…To determine whether hCDC14A localization changes upon perturbation of the F-actin cytoskeleton, we treated cells with blebbistatin, a myosin II inhibitor that inhibits F-actin formation. Blebbistatin treatment prompted all three tagged versions of hCDC14A to join F-actin remnants in relocalizing to peripheral regions of the cell ( We next monitored the distribution of endogenous hCDC14A with polyclonal antibodies that had been raised against the divergent C terminus of hCDC14A (26,27). These anti-hCDC14A antibodies costained the cell leading edge and the nearby actin filaments ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion

Chen

Uddin

Voit

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Cell adhesion and migration are highly dynamic biological processes that play important roles in organ development and cancer metastasis. Their tight regulation by small GTPases and protein phosphorylation make interrogation of these key processes of great importance. We now show that the conserved dualspecificity phosphatase human cell-division cycle 14A (hCDC14A) associates with the actin cytoskeleton of human cells. To understand hCDC14A function at this location, we manipulated native loci to ablate hCDC14A phosphatase activity (hCDC14A PD ) in untransformed hTERT-RPE1 and colorectal cancer (HCT116) cell lines and expressed the phosphatase in HeLa FRT T-Rex cells. Ectopic expression of hCDC14A induced stress fiber formation, whereas stress fibers were diminished in hCDC14A PD cells. hCDC14A PD cells displayed faster cell migration and less adhesion than wild-type controls. hCDC14A colocalized with the hCDC14A substrate kidneyand brain-expressed protein (KIBRA) at the cell leading edge and overexpression of KIBRA was able to reverse the phenotypes of hCDC14A PD cells. Finally, we show that ablation of hCDC14A activity increased the aggressive nature of cells in an in vitro tumor formation assay. Consistently, hCDC14A is down-regulated in many tumor tissues and reduced hCDC14A expression is correlated with poorer survival of patients with cancer, to suggest that hCDC14A may directly contribute to the metastatic potential of tumors. Thus, we have uncovered an unanticipated role for hCDC14A in cell migration and adhesion that is clearly distinct from the mitotic and cytokinesis functions of Cdc14/Flp1 in budding and fission yeast.CDC14 | cell migration | cell adhesion | phosphatase

show abstract

“…While MCM5 and ORC1 associate with both cyclin E and cyclin A, only ORC1 inhibits cyclin/CDK2 activity. CDC14 dephosphorylates certain CDK substrates and may counteract CDK-mediated phosphorylation of centrosomal substrates (58, 59). RBM14 has no connection to CDK2; it suppresses the assembly of centriolar protein complexes that would lead to the formation of extra centrioles.…”

Section: Discussionmentioning

confidence: 99%

Opposing post-translational modifications regulate Cep76 function to suppress centriole amplification

et al. 2016

View full text Add to dashboard Cite

Centrioles are critical for many cellular processes including cell division and cilia assembly. The number of centrioles within a cell is under strict control, and deregulation of centriole copy number is a hallmark of cancer. The molecular mechanisms that halt centriole amplification have not been fully elucidated. Here, we found that centrosomal protein of 76 kDa (Cep76), previously shown to restrain centriole amplification, interacts with cyclin-dependent kinase 2 (CDK2) and is a bona fide substrate of this kinase. Cep76 is preferentially phosphorylated by cyclin A/CDK2 at a single site S83, and this event is crucial to suppress centriole amplification in S phase. A novel Cep76 mutation S83C identified in a cancer patient fails to prevent centriole amplification. Mechanistically, Cep76 phosphorylation inhibits activation of polo-like kinase 1 (Plk1), thereby blocking premature centriole disengagement and subsequent amplification. Cep76 can also be acetylated, and enforced acetylation at K279 dampens the protein’s ability to inhibit amplification and precludes S83 phosphorylation. Acetylation of Cep76 normally occurs in G2 phase and correlates with loss of protein function. Our data suggest that temporal changes in posttranslational modifications of Cep76 during the cell cycle regulate its capacity to suppress centriole amplification, and its deregulation may contribute to malignancy.

show abstract

Human Cdc14A regulates Wee1 stability by counteracting CDK-mediated phosphorylation

Cited by 31 publications

References 43 publications

Overexpression of DOC-1R Inhibits Cell Cycle G1/S Transition by Repressing CDK2 Expression and Activation

Overexpression of DOC-1R Inhibits Cell Cycle G1/S Transition by Repressing CDK2 Expression and Activation

Human phosphatase CDC14A is recruited to the cell leading edge to regulate cell migration and adhesion

Opposing post-translational modifications regulate Cep76 function to suppress centriole amplification

Contact Info

Product

Resources

About