Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast

Abstract The final step in post-translational processing of Ras and Rho GTPases involves methylation of the prenylated cysteine residue by an isoprenylcysteine-O-carboxyl methyltransferase (ICMT). ICMT activity is essential for cell growth and development in higher eukaryotes, and inhibition of GTPa...

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Autores principales:	Alejandro Franco, Teresa Soto, Rebeca Martín-García, Marisa Madrid, Beatriz Vázquez-Marín, Jero Vicente-Soler, Pedro M. Coll, Mariano Gacto, Pilar Pérez, José Cansado
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/456d2353d713453aa2b34b2014f01f07
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spelling	oai:doaj.org-article:456d2353d713453aa2b34b2014f01f072021-12-02T11:40:21ZDistinct functional relevance of dynamic GTPase cysteine methylation in fission yeast10.1038/s41598-017-06053-x2045-2322https://doaj.org/article/456d2353d713453aa2b34b2014f01f072017-07-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-06053-xhttps://doaj.org/toc/2045-2322Abstract The final step in post-translational processing of Ras and Rho GTPases involves methylation of the prenylated cysteine residue by an isoprenylcysteine-O-carboxyl methyltransferase (ICMT). ICMT activity is essential for cell growth and development in higher eukaryotes, and inhibition of GTPase methylation has become an attractive target in cancer therapy to inactivate prenylated oncoproteins. However, the specificity and dynamics of the GTPase methylation process remain to be fully clarified. Notably, cells lacking Mam4, the ICMT ortholog in the fission yeast Schizosaccharomyces pombe, are viable. We have exploited this feature to analyze the role of methylation on GTPase localization and function. We show that methylation differentially affects GTPase membrane localization, being particularly relevant for plasma membrane tethering and downstream signaling of palmitoylated and farnesylated GTPases Ras1 and Rho2 lacking C-terminal polybasic motifs. Indeed, Ras1 and Rho2 cysteine methylation is required for proper regulation of differentiation elicited by MAPK Spk1 and for stress-dependent activation of the cell integrity pathway (CIP) and its main effector MAPK Pmk1. Further, Mam4 negatively regulates TORC2 signaling by a cross-inhibitory mechanism relying on Rho GTPase methylation. These results highlight the requirement for a tight control of GTPase methylation in vivo to allow adequate GTPase function.Alejandro FrancoTeresa SotoRebeca Martín-GarcíaMarisa MadridBeatriz Vázquez-MarínJero Vicente-SolerPedro M. CollMariano GactoPilar PérezJosé CansadoNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-14 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Alejandro Franco Teresa Soto Rebeca Martín-García Marisa Madrid Beatriz Vázquez-Marín Jero Vicente-Soler Pedro M. Coll Mariano Gacto Pilar Pérez José Cansado Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast
description	Abstract The final step in post-translational processing of Ras and Rho GTPases involves methylation of the prenylated cysteine residue by an isoprenylcysteine-O-carboxyl methyltransferase (ICMT). ICMT activity is essential for cell growth and development in higher eukaryotes, and inhibition of GTPase methylation has become an attractive target in cancer therapy to inactivate prenylated oncoproteins. However, the specificity and dynamics of the GTPase methylation process remain to be fully clarified. Notably, cells lacking Mam4, the ICMT ortholog in the fission yeast Schizosaccharomyces pombe, are viable. We have exploited this feature to analyze the role of methylation on GTPase localization and function. We show that methylation differentially affects GTPase membrane localization, being particularly relevant for plasma membrane tethering and downstream signaling of palmitoylated and farnesylated GTPases Ras1 and Rho2 lacking C-terminal polybasic motifs. Indeed, Ras1 and Rho2 cysteine methylation is required for proper regulation of differentiation elicited by MAPK Spk1 and for stress-dependent activation of the cell integrity pathway (CIP) and its main effector MAPK Pmk1. Further, Mam4 negatively regulates TORC2 signaling by a cross-inhibitory mechanism relying on Rho GTPase methylation. These results highlight the requirement for a tight control of GTPase methylation in vivo to allow adequate GTPase function.
format	article
author	Alejandro Franco Teresa Soto Rebeca Martín-García Marisa Madrid Beatriz Vázquez-Marín Jero Vicente-Soler Pedro M. Coll Mariano Gacto Pilar Pérez José Cansado
author_facet	Alejandro Franco Teresa Soto Rebeca Martín-García Marisa Madrid Beatriz Vázquez-Marín Jero Vicente-Soler Pedro M. Coll Mariano Gacto Pilar Pérez José Cansado
author_sort	Alejandro Franco
title	Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast
title_short	Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast
title_full	Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast
title_fullStr	Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast
title_full_unstemmed	Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast
title_sort	distinct functional relevance of dynamic gtpase cysteine methylation in fission yeast
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/456d2353d713453aa2b34b2014f01f07
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Distinct functional relevance of dynamic GTPase cysteine methylation in fission yeast

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