Interplay between microtubules, myosin filaments, and a multitude of integrin-mediated adhesions
2Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel
3Grenoble institute of Neuroscience, University Grenoble Alpes, Inserm U1216, Grenoble, France
Integrin-based adhesions – focal adhesions, fibrillar adhesions and podosomes – mediate transmembrane interactions between the cell's actin cytoskeleton and the extracellular matrix, critically participating in the processes of mechano-transduction/mechano-sensing, formation of matrix fibrils, and proteolytic matrix degradation, respectively. Besides the association with the actin cytoskeleton, integrin adhesions continuously interact with dynamic microtubules through the molecular complexes containing KANK family proteins. Here we show that breaking these interactions results in release of microtubule-associated Rho activator GEF-H1 from microtubules, which triggers activation of the Rho-ROCK signalling cascade and the assembly of myosin IIA and actin filaments (Rafiq NBM et al. Nat Mater. 2019, 18(6):638-649). The myosin IIA-driven actomyosin contractility, in turn, remodels the integrin-mediated adhesions in a differential fashion, promoting assembly and growth of the focal adhesions, but disassembly of the podosomes and fibrillar adhesions. Stimulating the interactions between microtubules and focal adhesions by local optogenetic activation of KANK1-mediated link results in focal adhesion centripetal sliding and consequent disassembly. Remarkably, GEF-H1-dependent Rho-ROCK-myosin II activation is required not only for the focal adhesion growth upon uncoupling from microtubules, but also for the focal adhesion disassembly induced by the optogenetic stimulation of microtubule targeting to the focal adhesions. Molecules involved in this process include, besides GEF-H1, kinases FAK and PAK, tubulin acetylase ATAT1, microtubule motor kinesin-1 and microtubule-associated actin polymerisation activator APC. Thus, microtubules function as sensory and regulatory elements, whose interactions with the integrin adhesions locally control formation of myosin filaments, which then affect adhesions closing the feedback loop.