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M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration

Collective cell migration is required for normal embryonic development and contributes to various biological processes, including wound healing and cancer cell invasion. The M-Ras GTPase and its effector, the Shoc2 scaffold, are proteins mutated in the developmental RASopathy Noonan syndrome, and, h...

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Autores principales: Kota, Pradeep, Terrell, Elizabeth M., Ritt, Daniel A., Insinna, Christine, Westlake, Christopher J., Morrison, Deborah K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397545/
https://www.ncbi.nlm.nih.gov/pubmed/30808747
http://dx.doi.org/10.1073/pnas.1805919116
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author Kota, Pradeep
Terrell, Elizabeth M.
Ritt, Daniel A.
Insinna, Christine
Westlake, Christopher J.
Morrison, Deborah K.
author_facet Kota, Pradeep
Terrell, Elizabeth M.
Ritt, Daniel A.
Insinna, Christine
Westlake, Christopher J.
Morrison, Deborah K.
author_sort Kota, Pradeep
collection PubMed
description Collective cell migration is required for normal embryonic development and contributes to various biological processes, including wound healing and cancer cell invasion. The M-Ras GTPase and its effector, the Shoc2 scaffold, are proteins mutated in the developmental RASopathy Noonan syndrome, and, here, we report that activated M-Ras recruits Shoc2 to cell surface junctions where M-Ras/Shoc2 signaling contributes to the dynamic regulation of cell–cell junction turnover required for collective cell migration. MCF10A cells expressing the dominant-inhibitory M-Ras(S27N) variant or those lacking Shoc2 exhibited reduced junction turnover and were unable to migrate effectively as a group. Through further depletion/reconstitution studies, we found that M-Ras/Shoc2 signaling contributes to junction turnover by modulating the E-cadherin/p120-catenin interaction and, in turn, the junctional expression of E-cadherin. The regulatory effect of the M-Ras/Shoc2 complex was mediated at least in part through the phosphoregulation of p120-catenin and required downstream ERK cascade activation. Strikingly, cells rescued with the Noonan-associated, myristoylated-Shoc2 mutant (Myr-Shoc2) displayed a gain-of-function (GOF) phenotype, with the cells exhibiting increased junction turnover and reduced E-cadherin/p120-catenin binding and migrating as a faster but less cohesive group. Consistent with these results, Noonan-associated C-Raf mutants that bypass the need for M-Ras/Shoc2 signaling exhibited a similar GOF phenotype when expressed in Shoc2-depleted MCF10A cells. Finally, expression of the Noonan-associated Myr-Shoc2 or C-Raf mutants, but not their WT counterparts, induced gastrulation defects indicative of aberrant cell migration in zebrafish embryos, further demonstrating the function of the M-Ras/Shoc2/ERK cascade signaling axis in the dynamic control of coordinated cell movement.
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spelling pubmed-63975452019-03-06 M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration Kota, Pradeep Terrell, Elizabeth M. Ritt, Daniel A. Insinna, Christine Westlake, Christopher J. Morrison, Deborah K. Proc Natl Acad Sci U S A PNAS Plus Collective cell migration is required for normal embryonic development and contributes to various biological processes, including wound healing and cancer cell invasion. The M-Ras GTPase and its effector, the Shoc2 scaffold, are proteins mutated in the developmental RASopathy Noonan syndrome, and, here, we report that activated M-Ras recruits Shoc2 to cell surface junctions where M-Ras/Shoc2 signaling contributes to the dynamic regulation of cell–cell junction turnover required for collective cell migration. MCF10A cells expressing the dominant-inhibitory M-Ras(S27N) variant or those lacking Shoc2 exhibited reduced junction turnover and were unable to migrate effectively as a group. Through further depletion/reconstitution studies, we found that M-Ras/Shoc2 signaling contributes to junction turnover by modulating the E-cadherin/p120-catenin interaction and, in turn, the junctional expression of E-cadherin. The regulatory effect of the M-Ras/Shoc2 complex was mediated at least in part through the phosphoregulation of p120-catenin and required downstream ERK cascade activation. Strikingly, cells rescued with the Noonan-associated, myristoylated-Shoc2 mutant (Myr-Shoc2) displayed a gain-of-function (GOF) phenotype, with the cells exhibiting increased junction turnover and reduced E-cadherin/p120-catenin binding and migrating as a faster but less cohesive group. Consistent with these results, Noonan-associated C-Raf mutants that bypass the need for M-Ras/Shoc2 signaling exhibited a similar GOF phenotype when expressed in Shoc2-depleted MCF10A cells. Finally, expression of the Noonan-associated Myr-Shoc2 or C-Raf mutants, but not their WT counterparts, induced gastrulation defects indicative of aberrant cell migration in zebrafish embryos, further demonstrating the function of the M-Ras/Shoc2/ERK cascade signaling axis in the dynamic control of coordinated cell movement. National Academy of Sciences 2019-02-26 2019-02-11 /pmc/articles/PMC6397545/ /pubmed/30808747 http://dx.doi.org/10.1073/pnas.1805919116 Text en Copyright © 2019 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle PNAS Plus
Kota, Pradeep
Terrell, Elizabeth M.
Ritt, Daniel A.
Insinna, Christine
Westlake, Christopher J.
Morrison, Deborah K.
M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration
title M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration
title_full M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration
title_fullStr M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration
title_full_unstemmed M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration
title_short M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell–cell adhesion during collective cell migration
title_sort m-ras/shoc2 signaling modulates e-cadherin turnover and cell–cell adhesion during collective cell migration
topic PNAS Plus
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6397545/
https://www.ncbi.nlm.nih.gov/pubmed/30808747
http://dx.doi.org/10.1073/pnas.1805919116
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