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M-Ras/Shoc2 signaling modulates E-cadherin turnover and cell-cell adhesion during collective cell migration
Pradeep Kota1, Elizabeth M Terrell2, Daniel A Ritt2
1Laboratory of Cell and Developmental Signaling, National Cancer Institute-Frederick, Frederick, MD 21702 pkota@email.unc.edu morrisod@mail.nih.gov.
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.
Insights
The M-Ras/Shoc2 signaling pathway regulates cell-cell junction dynamics crucial for collective cell migration. Mutations in this pathway, seen in Noonan syndrome, disrupt cell coordination during embryonic development.
Area of Science:
- Cell Biology
- Developmental Biology
- Molecular Signaling
Background:
- Collective cell migration is vital for embryonic development, wound healing, and cancer invasion.
- The M-Ras GTPase and Shoc2 scaffold protein are implicated in Noonan syndrome, a developmental disorder.
- Understanding the M-Ras/Shoc2 pathway's role in cell migration is critical for developmental biology and disease research.
Purpose of the Study:
- To investigate the role of M-Ras/Shoc2 signaling in regulating cell-cell junction dynamics during collective cell migration.
- To elucidate the molecular mechanisms by which M-Ras/Shoc2 influences junction turnover and cell motility.
- To examine the impact of Noonan syndrome-associated mutations in M-Ras/Shoc2 and C-Raf on cell migration and embryonic development.
Main Methods:
- Utilized MCF10A cell models with dominant-inhibitory M-Ras variants or Shoc2 depletion.
- Employed depletion/reconstitution studies to analyze M-Ras/Shoc2 signaling effects on E-cadherin/p120-catenin interactions.
- Investigated the role of ERK cascade activation and p120-catenin phosphorylation.
- Assessed the impact of Noonan syndrome-associated mutants (Myr-Shoc2, C-Raf) in cell culture and zebrafish gastrulation models.
Main Results:
- M-Ras/Shoc2 signaling is essential for dynamic cell-cell junction turnover and effective collective cell migration.
- M-Ras/Shoc2 modulates E-cadherin/p120-catenin interactions and junctional E-cadherin levels, partly via p120-catenin phosphoregulation and ERK activation.
- Noonan syndrome-associated Myr-Shoc2 and C-Raf mutants exhibit gain-of-function phenotypes, increasing junction turnover and impairing cell cohesion.
- Expression of these mutants in zebrafish embryos caused gastrulation defects, indicating aberrant cell migration.
Conclusions:
- The M-Ras/Shoc2/ERK signaling axis plays a crucial role in the dynamic regulation of cell-cell junctions required for coordinated cell movement.
- Aberrant M-Ras/Shoc2 signaling, as seen in Noonan syndrome, can lead to impaired collective cell migration and developmental defects.
- This study highlights the importance of precise regulation of cell-cell adhesion dynamics in embryonic development and disease pathogenesis.
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