P190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity

Scott R. Frank, Clemens P. Köllmann, Phi Luong, Giorgio G. Galli, Lihua Zou, André Bernards, Gad Getz, Raffaele A. Calogero, Morten Frödin, Steen H. Hansen*

*Corresponding author for this work

Research output: Contribution to journalArticle

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Abstract

ARH GAP35 encoding p190A RhoGAP is a cancer-associated gene with a mutation spectrum suggestive of a tumor-suppressor function. In this study, we demonstrate that loss of heterozygosity for ARH GAP35 occurs in human tumors. We sought to identify tumor-suppressor capacities for p190A RhoGAP (p190A) and its paralog p190B in epithelial cells. We reveal an essential role for p190A and p190B to promote contact inhibition of cell proliferation (CIP), a function that relies on RhoGAP activity. Unbiased mRNA sequencing analyses establish that p190A and p190B modulate expression of genes associated with the Hippo pathway. Accordingly, we determine that p190A and p190B induce CIP by repressing YAP-TEAD-regulated gene transcription through activation of LATS kinases and inhibition of the Rho-ROCK pathway. Finally, we demonstrate that loss of a single p190 paralog is sufficient to elicit nuclear translocation of YAP and perturb CIP in epithelial cells cultured in Matrigel. Collectively, our data reveal a novel mechanism consistent with a tumor-suppressor function for ARH GAP35.

Original languageEnglish (US)
Pages (from-to)3183-3201
Number of pages19
JournalJournal of Cell Biology
Volume217
Issue number9
DOIs
StatePublished - Sep 1 2018

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Contact Inhibition
Epithelial Cells
Cell Proliferation
Neoplasms
Long-Acting Thyroid Stimulator
Loss of Heterozygosity
Neoplasm Genes
Transcriptional Activation
Phosphotransferases
Gene Expression
Messenger RNA
Mutation
Genes

ASJC Scopus subject areas

  • Cell Biology

Cite this

Frank, S. R., Köllmann, C. P., Luong, P., Galli, G. G., Zou, L., Bernards, A., ... Hansen, S. H. (2018). P190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity. Journal of Cell Biology, 217(9), 3183-3201. https://doi.org/10.1083/jcb.201710058
Frank, Scott R. ; Köllmann, Clemens P. ; Luong, Phi ; Galli, Giorgio G. ; Zou, Lihua ; Bernards, André ; Getz, Gad ; Calogero, Raffaele A. ; Frödin, Morten ; Hansen, Steen H. / P190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity. In: Journal of Cell Biology. 2018 ; Vol. 217, No. 9. pp. 3183-3201.
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abstract = "ARH GAP35 encoding p190A RhoGAP is a cancer-associated gene with a mutation spectrum suggestive of a tumor-suppressor function. In this study, we demonstrate that loss of heterozygosity for ARH GAP35 occurs in human tumors. We sought to identify tumor-suppressor capacities for p190A RhoGAP (p190A) and its paralog p190B in epithelial cells. We reveal an essential role for p190A and p190B to promote contact inhibition of cell proliferation (CIP), a function that relies on RhoGAP activity. Unbiased mRNA sequencing analyses establish that p190A and p190B modulate expression of genes associated with the Hippo pathway. Accordingly, we determine that p190A and p190B induce CIP by repressing YAP-TEAD-regulated gene transcription through activation of LATS kinases and inhibition of the Rho-ROCK pathway. Finally, we demonstrate that loss of a single p190 paralog is sufficient to elicit nuclear translocation of YAP and perturb CIP in epithelial cells cultured in Matrigel. Collectively, our data reveal a novel mechanism consistent with a tumor-suppressor function for ARH GAP35.",
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Frank, SR, Köllmann, CP, Luong, P, Galli, GG, Zou, L, Bernards, A, Getz, G, Calogero, RA, Frödin, M & Hansen, SH 2018, 'P190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity', Journal of Cell Biology, vol. 217, no. 9, pp. 3183-3201. https://doi.org/10.1083/jcb.201710058

P190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity. / Frank, Scott R.; Köllmann, Clemens P.; Luong, Phi; Galli, Giorgio G.; Zou, Lihua; Bernards, André; Getz, Gad; Calogero, Raffaele A.; Frödin, Morten; Hansen, Steen H.

In: Journal of Cell Biology, Vol. 217, No. 9, 01.09.2018, p. 3183-3201.

Research output: Contribution to journalArticle

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T1 - P190 RhoGAP promotes contact inhibition in epithelial cells by repressing YAP activity

AU - Frank, Scott R.

AU - Köllmann, Clemens P.

AU - Luong, Phi

AU - Galli, Giorgio G.

AU - Zou, Lihua

AU - Bernards, André

AU - Getz, Gad

AU - Calogero, Raffaele A.

AU - Frödin, Morten

AU - Hansen, Steen H.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - ARH GAP35 encoding p190A RhoGAP is a cancer-associated gene with a mutation spectrum suggestive of a tumor-suppressor function. In this study, we demonstrate that loss of heterozygosity for ARH GAP35 occurs in human tumors. We sought to identify tumor-suppressor capacities for p190A RhoGAP (p190A) and its paralog p190B in epithelial cells. We reveal an essential role for p190A and p190B to promote contact inhibition of cell proliferation (CIP), a function that relies on RhoGAP activity. Unbiased mRNA sequencing analyses establish that p190A and p190B modulate expression of genes associated with the Hippo pathway. Accordingly, we determine that p190A and p190B induce CIP by repressing YAP-TEAD-regulated gene transcription through activation of LATS kinases and inhibition of the Rho-ROCK pathway. Finally, we demonstrate that loss of a single p190 paralog is sufficient to elicit nuclear translocation of YAP and perturb CIP in epithelial cells cultured in Matrigel. Collectively, our data reveal a novel mechanism consistent with a tumor-suppressor function for ARH GAP35.

AB - ARH GAP35 encoding p190A RhoGAP is a cancer-associated gene with a mutation spectrum suggestive of a tumor-suppressor function. In this study, we demonstrate that loss of heterozygosity for ARH GAP35 occurs in human tumors. We sought to identify tumor-suppressor capacities for p190A RhoGAP (p190A) and its paralog p190B in epithelial cells. We reveal an essential role for p190A and p190B to promote contact inhibition of cell proliferation (CIP), a function that relies on RhoGAP activity. Unbiased mRNA sequencing analyses establish that p190A and p190B modulate expression of genes associated with the Hippo pathway. Accordingly, we determine that p190A and p190B induce CIP by repressing YAP-TEAD-regulated gene transcription through activation of LATS kinases and inhibition of the Rho-ROCK pathway. Finally, we demonstrate that loss of a single p190 paralog is sufficient to elicit nuclear translocation of YAP and perturb CIP in epithelial cells cultured in Matrigel. Collectively, our data reveal a novel mechanism consistent with a tumor-suppressor function for ARH GAP35.

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