The ubiquitin-proteasome system regulates focal adhesions at the leading edge of migrating cells

Abstract

Cell migration requires the cyclical assembly and disassembly of focal adhesions. Adhesion induces phosphorylation of focal adhesion proteins, including Cas (Crk-associated substrate/p130Cas/BCAR1). However, Cas phosphorylation stimulates adhesion turnover. This raises the question of how adhesion assembly occurs against opposition from phospho-Cas. Here we show that suppressor of cytokine signaling 6 (SOCS6) and Cullin 5, two components of the CRL5SOCS6 ubiquitin ligase, inhibit Cas-dependent focal adhesion turnover at the front but not rear of migrating epithelial cells. The front focal adhesions contain phospho-Cas which recruits SOCS6. If SOCS6 cannot access focal adhesions, or if cullins or the proteasome are inhibited, adhesion disassembly is stimulated. This suggests that the localized targeting of phospho-Cas within adhesions by CRL5SOCS6 and concurrent cullin and proteasome activity provide a negative feedback loop, ensuring that adhesion assembly predominates over disassembly at the leading edge. By this mechanism, ubiquitination provides a new level of spatio-temporal control over cell migration.DOI: http://dx.doi.org/10.7554/eLife.17440.001

Dual Targeting of Mesenchymal and Amoeboid Motility Hinders Metastatic Behavior

“…However, these cells also saw an increase in long fibrillar adhesions (Fig.S3D). These findings suggest that NEDD9 is also required for the disassembly of fibrillar adhesions similar to vinculin (43), which regulates the recruitment and release of focal adhesion proteins in a force-dependent manner (44). The role of NEDD9/HEF1 as a sensor of altered adhesion states has been previously reported (45).…”

Optogenetic control of the Dab1 signaling pathway

“…The LED array for illuminating cells for biochemistry was made according to the methods as described4546. Briefly, 6 LED bulbs and the BuckPuck LED driver were connected to an Arduino Uno microcontroller.…”

Cell‐Cycle‐Dependent Regulation of Cell Adhesions: Adhering to the Schedule

“…FAK, ERK, paxillin, the myosin light chain kinase, and p130Cas, have all been shown to be critical for focal adhesion disassembly because the absence of these proteins leads to more stable structures . More recent work, focused specifically on p130Cas, demonstrated that adhesion‐mediated tyrosine phosphorylation of this protein recruits an E3 ubiquitin ligase leading to p130cas degradation . Since the absence of p130Cas promotes focal adhesion stability, its selective degradation in some adhesions but not others provides a potential mechanism for the differential behavior of neighboring adhesions at the front of migrating cells.…”

“…Since the absence of p130Cas promotes focal adhesion stability, its selective degradation in some adhesions but not others provides a potential mechanism for the differential behavior of neighboring adhesions at the front of migrating cells. In this scenario, disassembly is favored for those adhesions containing p130Cas, whereas p130Cas destruction promotes adhesion survival and growth . The mechanism by which adhesions are disassembled downstream from p130Cas has not been established.…”