Symmetry breaking in spreading RAT2 fibroblasts requires the MAPK/ERK pathway scaffold RACK1 that integrates FAK, p190A-RhoGAP and ERK2 signaling
Language English Country Netherlands Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
27212270
DOI
10.1016/j.bbamcr.2016.05.013
PII: S0167-4889(16)30157-4
Knihovny.cz E-resources
- Keywords
- ERK, FAK, Feed-forward loop, Polarity, RACK1, p190A-RhoGAP,
- MeSH
- Actins metabolism MeSH
- Models, Biological MeSH
- Cell Adhesion MeSH
- Phenotype MeSH
- Fibroblasts cytology enzymology metabolism MeSH
- Focal Adhesion Protein-Tyrosine Kinases metabolism MeSH
- Gene Knockdown Techniques MeSH
- Rats MeSH
- MAP Kinase Signaling System * MeSH
- Mitogen-Activated Protein Kinase 1 metabolism MeSH
- Cell Movement MeSH
- GTP-Binding Proteins deficiency metabolism MeSH
- Receptors for Activated C Kinase MeSH
- Repressor Proteins metabolism MeSH
- Cell Shape MeSH
- Gene Silencing MeSH
- Animals MeSH
- Check Tag
- Rats MeSH
- Animals MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- Actins MeSH
- Arhgap35 protein, rat MeSH Browser
- Focal Adhesion Protein-Tyrosine Kinases MeSH
- Mitogen-Activated Protein Kinase 1 MeSH
- GTP-Binding Proteins MeSH
- RACK1 protein, rat MeSH Browser
- Receptors for Activated C Kinase MeSH
- Repressor Proteins MeSH
The spreading of adhering cells is a morphogenetic process during which cells break spherical or radial symmetry and adopt migratory polarity with spatially segregated protruding cell front and non-protruding cell rear. The organization and regulation of these symmetry-breaking events, which are both complex and stochastic, are not fully understood. Here we show that in radially spreading cells, symmetry breaking commences with the development of discrete non-protruding regions characterized by large but sparse focal adhesions and long peripheral actin bundles. Establishment of this non-protruding static region specifies the distally oriented protruding cell front and thus determines the polarity axis and the direction of cell migration. The development of non-protruding regions requires ERK2 and the ERK pathway scaffold protein RACK1. RACK1 promotes adhesion-mediated activation of ERK2 that in turn inhibits p190A-RhoGAP signaling by reducing the peripheral localization of p190A-RhoGAP. We propose that sustained ERK signaling at the prospective cell rear induces p190A-RhoGAP depletion from the cell periphery resulting in peripheral actin bundles and cell rear formation. Since cell adhesion activates both ERK and p190A-RhoGAP signaling this constitutes a spatially confined incoherent feed-forward signaling circuit.
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