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Integrin: signalling from the tail and the hub

Final Report Summary - SIGNAL2THEHUB (Integrin: signalling from the tail and the hub)

Our lab studies the molecular mechanisms of integrin-mediated cell-matrix adhesion. Integrin-mediated adhesion is essential for key cellular processes including migration, proliferation, survival and differentiation. Integrin adhesion is triggered by altering the conformation of integrins that allows ligand binding. Ligand bound integrins cluster and assembley large protein networks that transfer chemical and mechanical signals bidirectionally across the plasma membrane (from the outside to the inside and vice versa). The protein assembly recruited to integrins tails translates biophysical information into biochemistry and ensures that integrins are regularly endocytosed to test their integrity before they are recycled back to the cell surface for reuse.

We study how integrins become activated, how the activation step is reversed, which proteins are recruited to integrin adhesion sites, to which extent the protein composition and the protein networking varies between adhesion sites established by different integrins, and how integrins crosstalk with growth factor receptor signaling.

In the past years, we made tremendous progress in elucidating how two highly different integrin classes that bind the same ligand (fibronectin) differ in their adhesome composition, adhesion site assembly and force generation. Instrumental for these studies was the generation of uniquely engineered cells that express very specific integrin classes. The results obtained with these cell model systems revealed that adhesion size does not correlate with the duration and strength of force production. We also succeeded to define integrin-dependent and -independent functions of the integrin-binding protein Kindlin-1 in keratinocytes that provided an explanation why humans lacking the Kindlin-1 gene are prone to skin cancer. Finally, we identified new proteins that interact with integrin tails to maintain integrins in an inactive state, and demonstrated that Kindlin are indispensable for non-hematopoietic cells and how Kindlin mediates adhesion and cell spreading.