Integrins,cell surface receptors that play a major role in communication between the intracellular and extracellular environments, affect cellular processes such as adhesion, migration, proliferation, and survival. Integrins are critically important in developmental events, tissue maintenance, immune surveillance, and wound healing. Integrins also play key roles in diseases such as cancer, in which the interaction of tumor cells with their environment has far-reaching implications in tumor invasion and metastasis.

Upon binding of extracellular matrix (ECM), integrins cluster and recruit large signaling complexes to their cytoplasmic face that lead to alterations in both the actin cytoskeleton and gene expression. In turn, intracellular components can modulate the binding of integrins to the ECM. Integrins sense and respond to diverse cues, driving a wide array of possible cell behaviors. Notably, a relatively small number of signaling cascades participate in integrin-mediated signaling. Highly controlled regulation and cross-talk is required in order for these signaling modules to produce the appropriate behavioral output.

Scaffolding proteins, which mediate physical interactions with multiple protein partners, play an important role in signal integration by bringing together signaling molecules in a spatially and temporally regulated manner. One focus of our research is the molecular scaffold PINCH, a protein that we have shown to function in the coordination of integrin signaling with Jun kinase signaling (Kadrmas et. al., JCB 2004). We have identified a number of protein partners that associate with PINCH, and we are currently working toward a molecular understanding of how binding of these partners contributes to integrin function, both in development and disease.