Differential regulation of the Hippo pathway by adherens junctions and apical–basal cell polarity modules

Yang, Wen-Chi; Graves, Hillary K.; Moya, Iván M.; Tao, Chunyao; Hamaratoǧlu, Fisun; Gladden, Andrew B.; Halder, Georg

doi:10.1073/pnas.1420850112

Cited by 119 publications

(136 citation statements)

References 47 publications

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“…While there are remarkable similarities between the Hippo pathways present in flies and mammals, there are also notable differences (Klezovitch and Vasioukhin 2015;Yang et al 2015). Hence, to determine whether DLG5 function in negative regulation of Hippo signaling is evolutionarily conserved, we used RNAi-mediated knockdown to analyze the signaling role of Dlg5 in flies.…”

Section: Dlg5 Inhibits Hippo Signaling During Fly Developmentmentioning

confidence: 99%

“…To confirm whether expression of the dlg5 RNAi constructs resulted in misregulation of the Hippo pathway, we monitored Yki (Drosophila YAP/TAZ ortholog) activity using an established ex-LacZ reporter (Yang et al 2015). Expression of dlg5 RNAi using either engrailed or decapentaplegic drivers resulted in reduced LacZ staining (Fig.…”

Section: Dlg5 Inhibits Hippo Signaling During Fly Developmentmentioning

confidence: 99%

“…2), our findings suggested an important role of DLG5 in Hippo pathway regulation. However, prominent apical-basal cell polarity defects are present in Dlg5 −/− embryos (Nechiporuk et al 2007), and loss of apical-basal cell polarity may indirectly impact Hippo signaling, although general loss of cell polarity usually results in inactivation of the Hippo pathway (Boggiano and Fehon 2012;Szymaniak et al 2015;Yang et al 2015). Therefore, to rule out an indirect effect of Dlg5 inactivation on Hippo signaling due to apical-basal cell polarity defects in Dlg5 −/− embryos, we analyzed Hippo signaling in Dlg5…”

Section: Dlg5 Negatively Regulates Hippo Signaling In Nonpolarized Momentioning

confidence: 99%

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DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

et al. 2016

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Disruption of apical-basal polarity is implicated in developmental disorders and cancer; however, the mechanisms connecting cell polarity proteins with intracellular signaling pathways are largely unknown. We determined previously that membrane-associated guanylate kinase (MAGUK) protein discs large homolog 5 (DLG5) functions in cell polarity and regulates cellular proliferation and differentiation via undefined mechanisms. We report here that DLG5 functions as an evolutionarily conserved scaffold and negative regulator of Hippo signaling, which controls organ size through the modulation of cell proliferation and differentiation. Affinity purification/mass spectrometry revealed a critical role of DLG5 in the formation of protein assemblies containing core Hippo kinases mammalian ste20 homologs 1/2 (MST1/2) and Par-1 polarity proteins microtubule affinity-regulating kinases 1/2/3 (MARK1/2/3). Consistent with this finding, Hippo signaling is markedly hyperactive in mammalian Dlg5 −/− tissues and cells in vivo and ex vivo and in Drosophila upon dlg5 knockdown. Conditional deletion of Mst1/2 fully rescued the phenotypes of brain-specific Dlg5 knockout mice. Dlg5 also interacts genetically with Hippo effectors Yap1/Taz. Mechanistically, we show that DLG5 inhibits the association between MST1/2 and large tumor suppressor homologs 1/2 (LATS1/2), uses its scaffolding function to link MST1/2 with MARK3, and inhibits MST1/2 kinase activity. These data reveal a direct connection between cell polarity proteins and Hippo, which is essential for proper development of multicellular organisms.

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Section: Dlg5 Inhibits Hippo Signaling During Fly Developmentmentioning

confidence: 99%

Section: Dlg5 Inhibits Hippo Signaling During Fly Developmentmentioning

confidence: 99%

Section: Dlg5 Negatively Regulates Hippo Signaling In Nonpolarized Momentioning

confidence: 99%

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DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

et al. 2016

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“…19 Three apical-basal polarity complexes have been identified to date, including the CRB (Crumbs) complex (CRB/PATJ/PALS1), PAR complex (PAR3/PAR6/aPKC) and Scribble complex (SCRIB/DLG/LGL). These complexes work together to maintain apical-basal polarity.…”

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confidence: 99%

CRB3 regulates contact inhibition by activating the Hippo pathway in mammary epithelial cells

Mao

Wang

et al. 2017

Cell Death Dis

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The loss of contact inhibition is a hallmark of cancer cells. The Hippo pathway has recently been shown to be an important regulator of contact inhibition, and the cell apical polarity determinant protein CRB3 has been suggested to be involved in Hippo signalling. However, whether CRB3 regulates contact inhibition in mammary cells remains unclear, and the underlying mechanisms have not been elucidated. As shown in the present study, CRB3 decreases cell proliferation, promotes apoptosis, and enhances the formation of tight and adherens junctions. Furthermore, we report for the first time that CRB3 acts as an upstream regulator of the Hippo pathway to regulate contact inhibition by recruiting other Hippo molecules, such as Kibra and/or FRMD6, in mammary epithelial cells. In addition, CRB3 inhibits tumour growth in vivo. Collectively, the present study increases our understanding of the Hippo pathway and provides an important theoretical basis for exploring new avenues for breast cancer treatment.

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“…A variety of signals have been reported to either activate or inhibit the Hippo kinase cascade. In epithelial cells, apical-basal polarity regulates activities of the Hippo pathway through interactions between the upstream components and intercellular junction-associated proteins in response to cell-cell contact (40). Recent reports found that serum deprivation or energy stress also activates the Hippo pathway (41,42).…”

Section: Discussionmentioning

confidence: 99%

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

Kong

Shao

et al. 2017

Molecular Cancer Research

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In several squamous cell carcinoma (SCC) cells, it has been previously observed that induction of the S100 calcium-binding protein A7 (S100A7) is repressed by YAP via the Hippo pathway. This report now demonstrates that S100A7 also represses YAP expression and activity by DNp63 in cancer cells. Stable overexpression of S100A7 activates the NFkB pathway and inhibits the expression of DNp63. Caffeic acid phenethyl ester (CAPE), as a specific inhibitor of NFkB, counteracts the inhibitory effect of S100A7 on the expression of DNp63 and its target genes. Depletion of S100A7 significantly promotes DNp63 expression. These data indicate that S100A7 acts as a suppressor of DNp63. Mechanistic examination finds that DNp63 not only directly binds to the region of YAP promoter and induces its expression, but also inhibits the Hippo pathway and enhances YAP activity. Importantly, either the positive correlation between S100A7 and YAP phosphorylation at S127 or the negative correlation between S100A7 and DNp63 is also observed in skin SCC tissues. Chemosensitivity analysis reveals that S100A7 enhances cancer cells' resistance by inhibition of YAP expression and activity. These results demonstrate that S100A7 is an upstream modulator of the Hippo pathway and extend our understanding of S100A7 functions in cancer.Implications: S100A7 is a new upstream regulator of the Hippo signaling pathway and reduces chemosensitivity of SCC cells through inhibitions of YAP expression and activity.

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Differential regulation of the Hippo pathway by adherens junctions and apical–basal cell polarity modules

Cited by 119 publications

References 47 publications

DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

DLG5 connects cell polarity and Hippo signaling protein networks by linking PAR-1 with MST1/2

CRB3 regulates contact inhibition by activating the Hippo pathway in mammary epithelial cells

YAP Expression and Activity Are Suppressed by S100A7 via p65/NFκB-mediated Repression of ΔNp63

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