Cell adaptive response to extracellular matrix density is controlled by ICAP-1–dependent β1-integrin affinity

Abstract

Cell migration is an integrated process requiring the continuous coordinated assembly and disassembly of adhesion structures. How cells orchestrate adhesion turnover is only partially understood. We provide evidence for a novel mechanistic insight into focal adhesion (FA) dynamics by demonstrating that integrin cytoplasmic domain–associated protein 1 (ICAP-1) slows down FA assembly. Live cell imaging, which was performed in both Icap-1–deficient mouse embryonic fibroblasts and cells expressing active β1 integrin, shows that the integrin high affinity state favored by talin is antagonistically controlled by ICAP-1. This affinity switch results in modulation in the speed of FA assembly and, consequently, of cell spreading and migration. Unexpectedly, the ICAP-1–dependent decrease in integrin affinity allows cell sensing of matrix surface density, suggesting that integrin conformational changes are important in mechanotransduction. Our results clarify the function of ICAP-1 in cell adhesion and highlight the central role it plays in the cell's integrated response to the extracellular microenvironment.

Podosome-type adhesions and focal adhesions, so alike yet so different

“…Katz , 2000 et al Moreover, increase in substrate density accelerates focal adhesion assembly, a process that is dependent on ICAP-1. This allows the matrix surface density sensing by the cell permitting its adaptive response to changes in the properties of the ECM (Millon-Fremillon , 2008 et al ).…”

Mammary-derived growth inhibitor (MDGI) interacts with integrin α-subunits and suppresses integrin activity and invasion

“…Proteins binding to the b-subunit like talin and kindlins function to activate integrins, whereas negative regulators include proteins like ICAP-1, Filamin and Dok1, which can compete with talin for overlapping binding site on integrin cytoplasmic b-tail (Bouvard et al, 2003;Wegener et al, 2007;Millon-Fre´millon et al, 2008;Takala et al, 2008). Thus, significant advances have been made in our understanding of the role of b-tail in regulation of integrin activation.…”

La taline

“…Diverses études ont mis en évidence la régulation de l'interaction taline/intégrine par des adaptateurs à domaines PTB, domaines caractérisés par leur capacité à reconnaître les motifs NPXY présents en particulier dans les séquences cytoplasmiques des intégrines. Tandis que la taline peut lier différentes sous-unités des intégrines, la protéine ICAP-1 (integrin cytoplasmic domainassociated protein-1) qui possède un domaine PTB semble inhiber spécifique-ment la liaison de la taline à la sousunité 1 , régulant ainsi l'assemblage des adhérences focales, l'adhérence et la migration cellulaires, ainsi que la perception de la densité de la matrice extracellulaire [9]. D'autres compétitions ont été décrites entre la filamine et la taline pour la liaison à la sous-unité 7 [10], entre la tensine et la taline pour la liaison à 1 -un mécanisme probable de régula-tion de la fibrillogenèse de fibronectine [11] -ou entre la taline et Dock pour 3 [12].…”