Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH
Volume 1863, Issue 9, Pages 2189-2200Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbamcr.2016.05.013
Keywords
RACK1; ERK; FAK; p190A-RhoGAP; Polarity; Feed-forward loop
Categories
Funding
- Czech Science Foundation grant [13-06405S]
- EU FP7 Marie Curie IRG grant [231086]
- institutional research concept [RVO 61388971]
- J.E. Purkynje fellowship
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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. (C) 2016 Elsevier B.V. All rights reserved.
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