Integrins form a large family of transmembrane cell adhesion receptors, formed by β heterodimers and involved in different physiological processes such as hemostasis, cell migration, and pathological conditions like cancer, Glanzmann thrombasthenia hereditary hemorrhagic disorder and chronic inflammation… Cells express different integrins (classified by the type of the β chain: β1, β2, β3…) which allow them to attach, spread and migrate on different substrates. A large body of data show that integrin function is regulated by protein-protein interactions between the integrin cytoplasmic domain and cytosolic proteins. Hence, integrin activation was shown by our work and others to be directly driven by the binding of cytoskeletal proteins such as talin and kindlin to the β integrin cytoplasmic tail. The role of talin in the integrin activation process is pretty well understood: We and others have shown that talin binding to the β integrin tail causes a conformational change of the integrin heterodimer, increasing its affinity for its extracellular ligand and binding, thus allowing cell adhesion (Figure 1). Kindlin’s role, however, is still unclear as Kindlin seems to have an integrin-specific effect. Recently, our published work on integrin activation1 clearly showed an interesting difference between β1 and β3 integrins expressed in the same cells, regarding their activation by talin and its co-operative partner, kindlin. While β3 integrins are highly activated by the co-expression of kindlin and talin (Figure 2B), 1 integrins are inhibited when kindlin is expressed in presence of talin (Figure 2A). This observation suggests that kindlin could act as an integrin switcher, by activating β3 integrins and inhibiting β1 integrins. Previous studies on different cancer cells have revealed a similar integrin switch behavior, where cancerous cells differentially use integrin sub-families to undergo epithelial-mesenchymal transition(EMT) and become metastatic. This “integrin switch” process is poorly understood at its molecularlevel, but considered a hallmark of the metastatic progression of cancer. Our hypothesis is that kindlinis a key player in enabling the integrin switch by inactivating β1 integrins and activating β3 integrins.Thus, allowing the metastatic cells to acquire a β3 integrin–dependent migratory phenotype.Therefore, our project aims at studying the molecular mechanism that explains the difference inresponse of β1 and β3 integrins in presence of kindlin. In addition, we will assess the precise role playedby kindlin as a co-activator or a repressor for other important cancer-related integrins (such as β2, β5…).