Biophysical Society Thematic Meeting | Singapore

Mechanobiology of Disease

Tuesday Speaker Abstracts

Integrin-dependent Mechano-signaling, Switching Integrin Behavior by Alternative Splicing and Posttranslational Modification Bernhard Wehrle-Haller . University of Geneva, Geneva, Switzerland. ß1-integrin-dependent cell-matrix adhesions provide anchorage to the extracellular matrix, as well as signaling for cell migration, survival and proliferation. On the other hand, the a5ß1 integrin has also a specific role in the deposition and re-organization of fibronectin fibrils in the extracellular space, which is critical for tissue formation, regeneration, but also relevant to pathologies such as fibrosis or cancer. How integrins can switch between the adhesion, signaling and fibronectin remodeling is not understood. ß1-integrin function is controlled allosterically by ligand binding to the extracellular domain and recruitment of cytoskeletal adapter proteins like talin and kindlin to the cytoplasmic tail. Differential recruitment of talin and kindlin isoforms have been linked to different types of cell-matrix adhesions, as well as alternatively spliced cytoplasmic domains, providing a plausible hypothesis that selective adapter recruitment controls and allows switching integrin function. With a fluorescently tagged ß1-integrin, we have analyzed the dynamics and signaling capacities of the commonly expressed ß1A-integrin, as well as the alternatively spliced ß1D-integrin, exclusively expressed in differentiated muscle. Interestingly, the distinct dynamics of these two splice variants is linked to differences in signaling rather than ligand or adapter binding affinities. This concept is also found in ß3- integrins, in which phosphorylation of the cytoplasmic domain is controlling the dynamic of integrin adhesions and thus cell motility. Our data provide a conceptual framework, how posttranslational modifications of the integrin cytoplasmic tail allow switching between integrin functions critical for cell adhesion and mechano-signaling, but also remodeling of the extracellular matrix. Interestingly the latter switch is coupled to the metabolic state of the cell, providing an unexpected regulation of integrin-dependent functions during proliferation and differentiation or pathologies such as fibrosis and cancer.

10