Research ArticleCell Biology

Cytokinesis involves a nontranscriptional function of the Hippo pathway effector YAP

Sci. Signal.  01 Mar 2016:
Vol. 9, Issue 417, pp. ra23
DOI: 10.1126/scisignal.aaa9227

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Separating dividing cells into two

By activating genes involved in cell growth and proliferation, the transcriptional coactivator YAP can act as a tumor promoter. In some contexts, however, YAP can instead act as a tumor suppressor. Bui et al. found that in mitotic cells, a kinase that promotes cell cycle progression phosphorylated YAP, and YAP was localized to subcellular structures involved in dividing cells into two, a process called cytokinesis. Furthermore, localization of YAP at these structures ensured the proper localization of other proteins necessary for cytokinesis. Cells deficient in YAP or that expressed a nonphosphorylatable form of YAP were more likely to have an abnormal number of chromosomes, a condition that can give rise to tumors. These results provide a potential mechanism to explain the tumor-suppressive activity of YAP (see also Pfeifer).

Abstract

YAP is a transcriptional coactivator that controls organ expansion and differentiation and is inhibited by the Hippo pathway in cells in interphase. Here, we demonstrated that, during mitosis, YAP localized to the midbody and spindle, subcellular structures that are involved in cytokinesis, the process by which contraction of the cytoskeleton produces two daughter cells. Furthermore, YAP was phosphorylated by CDK1, a kinase that promotes cell cycle progression. Knockdown of YAP by shRNA or expression of a nonphosphorylatable form of YAP delayed the separation of daughter cells (called abscission) and induced a cytokinesis phenotype associated with increased contractile force, membrane blebbing and bulges, and abnormal spindle orientation. Consequently, these defects led to an increased frequency of multinucleation, micronuclei, and aneuploidy. YAP was required for proper localization of proteins that regulate contraction during cytokinesis, including ECT2, MgcRacGap, Anillin, and RHOA. In addition, depletion of YAP increased the phosphorylation of myosin light chain, which would be expected to activate the contractile activity of myosin II, the molecular motor involved in cytokinesis. The polarity scaffold protein PATJ coprecipitated with YAP and colocalized with YAP at the cytokinesis midbody, and knockdown of PATJ phenocopied the cytokinetic defects and spindle orientation alterations induced by either YAP depletion or expression of a nonphosphorylatable YAP mutant. Together, these results reveal an unanticipated role for YAP in the proper organization of the cytokinesis machinery during mitosis through interaction with the polarity protein PATJ.

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