title: 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 CRL5SOCS6ubiquitin 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 CRL5SOCS6and 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.
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Anjali
authors.initials: A
authors.lastname: Teckchandani
authors.affiliation: Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, United States.
authors.forename: Jonathan A
authors.identifier: 0000-0002-8626-7827
authors.initials: JA
authors.lastname: Cooper
mesh_terms: D002460:Cell Line; D002465:Cell Movement; D050719:Crk-Associated Substrate Protein / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D004847:Epithelial Cells / Q000502:physiology*; D022001:Focal Adhesions / Q000378:metabolism*; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D025801:Ubiquitin / Q000378:metabolism*
chemical_list: C496871:CUL5 protein, human; D050719:Crk-Associated Substrate Protein; D044842:Cullin Proteins; C473085:SOCS6 protein, human; D050826:Suppressor of Cytokine Signaling Proteins; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex
keywords: cell adhesion; cell biology; cell signaling; human; ubiquitin