Biophysical Society Thematic Meeting

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.