Cell cycle regulation of Rho signaling pathways

David, Muriel D.; Petit, D.; Bertoglio, Jacques

doi:10.4161/cc.21088

Cited by 67 publications

(54 citation statements)

References 91 publications

(134 reference statements)

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“…One possibility is that hCDC14A dephosphorylates actin modulators such as the guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that regulate the activity of actin controlling small GTPases. Indeed, components of Rho GTPase pathways such as the nucleotide exchange factor GEF-H1, MyoGEF, RacGAP, and mDia3 are phosphorylated by the mitotic kinases CDK1, Polo kinase 1, and Aurora kinases (48)(49)(50)(51)(52). Because hCDC14A is a proline-directed phosphatase (31), it is plausible that it counteracts a proline-directed kinase such as CDK1.…”

Section: Discussionmentioning

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.

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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

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Section: Discussionmentioning

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.

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“…It suggests that Nav1.5 might affect the stability of the RhoA protein. Many post-transcriptional and post-translational events occur in cells such as phosphorylation, transglutamination, palmitoylation, AMPylation, isoprenylation, and ubiquitylation, and these modifications determine the distribution and life cycle of RhoA (28,29). Described mechanisms governing the stability of Rho proteins include phosphorylation of serine 188 on RhoA that protect against ubiquitin-mediated proteasomal degradation and geranylgeranylation which facilitates proteasomal degradation of Rho (30,31).…”

Section: Discussionmentioning

confidence: 99%

The small GTPase RhoA regulates the expression and function of the sodium channel Nav1.5 in breast cancer cells

Dulong

Fang

Gest

et al. 2013

International Journal of Oncology

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Abstract. Voltage-gated Na + channels (VGSCs) are highly expressed in several types of carcinomas including breast, prostate and lung cancers as well as in mesothelioma and cervical cancers. Although the VGSCs activity is considered crucial for the potentiation of cancer cell migration and invasion, the mechanisms responsible for their functional expression and regulation in cancer cells remain unclear. In the present study, the role of the small GTPase RhoA in the regulation of expression and function of the Nav1.5 channel in the breast cancer cell lines MDA-MB 231 and MCF-7 was investigated. RhoA silencing significantly reduced both Nav1.5 channel expression and sodium current indicating that RhoA exerts a stimulatory effect on the synthesis of an active form of Nav1.5 channel in cancer cells. The inhibition of Nav1.5 expression dramatically reduced both cell invasion and proliferation. In addition, a decrease of RhoA protein levels induced by Nav1.5 silencing was observed. Altogether, these findings revealed: i) the key role of the small GTPase RhoA in upregulation of Nav1.5 channel expression and tumor aggressiveness, and ii) the existence of a positive feedback of Nav1.5 channels on RhoA protein levels. IntroductionBreast cancer is the most commonly occurring cancer in women. Each year approximately one million of new cases occurred in the world, 25-40% of patients developing metastasis and dying from cancer (1,2). Many problems remain in its clinical management which is generally related to the malignancy types and drug resistance mechanisms as well as metastasis development. Additional investigations to understand the physiopathology of breast cancer are urgently necessary to develop new therapies based on new targets involved in cancer cell invasion and proliferation.In previous studies we have already demonstrated that the upregulation and activation of the small GTPase RhoA or RhoC contribute to cell invasion leading to breast cancer metastasis (3,4). RhoA signaling pathways are implicated in the activation of FAK, Akt/PI3K, p38MAPK and MLCK, which have been shown to be responsible for cytoskeleton actin reorganization, cell adhesion, motility, migration and invasion (5-9). In many types of cancers, RhoA appears to be overexpressed and/or constitutively activated (10,11), and considered to be a negative clinical prognosis marker (10,12,13).Recently, it has been shown that the voltage-gated Na + channels (VGSCs) could be an accelerating factor in malignant cancers (14-17). VGSCs are membrane panning proteins expressed in a wide variety of excitable and non-excitable cells, as well as in many carcinomas including breast cancer (18,19). VGSCs mainly mediate rapid and transient Na + influx into cells and are classically responsible for generation and propagation of action potential. In cancer cells, overexpression of VGSCs and/or their upregulation has been observed. In particular, the Nav1.5 channel type correlates with cancer cell invasion (20-22). Although it seems that the neonatal isoform of Nav1.5 ch...

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“…In mitotic entry (G2-M transition), Rac1 activates the CyclinB/Cdk1 complex by a pathway involving p21-activated kinases (PAKs) and the mitotic kinases AuroraA and Polo-like kinase 1 (Plk1)[62][63][64]. Finally, RhoA plays a key role in actin reorganization in mitosis, including the regulation of mitotic cell rounding and contractile ring formation (for a review, see[65])(Figure 16.6).…”

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confidence: 98%