PUBLICATION
M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell-cell adhesion during collective cell migration
- Authors
- Kota, P., Terrell, E.M., Ritt, D.A., Insinna, C., Westlake, C.J., Morrison, D.K.
- ID
- ZDB-PUB-190228-1
- Date
- 2019
- Source
- Proceedings of the National Academy of Sciences of the United States of America 116: 3536-3545 (Journal)
- Registered Authors
- Keywords
- C-Raf, M-Ras, Noonan syndrome, Shoc2, collective cell migration
- MeSH Terms
-
- Zebrafish/genetics
- Gain of Function Mutation/genetics
- Cell Adhesion/genetics*
- Cell Movement/genetics*
- Gastrulation/genetics
- Humans
- Noonan Syndrome/genetics
- Noonan Syndrome/physiopathology
- Cadherins/genetics
- Intracellular Signaling Peptides and Proteins/genetics*
- MAP Kinase Signaling System/genetics
- Animals
- Monomeric GTP-Binding Proteins/genetics*
- Protein Binding
- Embryonic Development/genetics*
- PubMed
- 30808747 Full text @ Proc. Natl. Acad. Sci. USA
Citation
Kota, P., Terrell, E.M., Ritt, D.A., Insinna, C., Westlake, C.J., Morrison, D.K. (2019) M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell-cell adhesion during collective cell migration. Proceedings of the National Academy of Sciences of the United States of America. 116:3536-3545.
Abstract
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-RasS27N 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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping