The integrin family of adhesion receptors provides a dynamic, tightly regulated link between extracellular matrix (or cellular counter-receptors) and intracellular cytoskeletal and signaling networks, enabling cells to sense and respond to their chemical and physical environment. Integrin-mediated cell adhesion is thus a key regulator of cell morphology, proliferation, migration, and differentiation, and controls tissue morphogenesis, angiogenesis, wound healing, hemostasis and the immune response. Perturbation of normal integrin adhesion and signaling contributes to a range of human diseases, most notably cardiovascular disease, inflammatory disorders and cancer.

Signaling to and from Integrins

Understanding the protein interaction networks that govern signaling to and from integrins is a major topic of research in the Calderwood lab. We, and others, have shown that direct binding of signaling, cytoskeletal and adaptor proteins to the short integrin cytoplasmic tails regulates integrin affinity for extracellular ligands, influences integrin clustering into adhesive structures and controls integrin recycling. Tail-binding proteins also link ligand-bound integrins to the actin cytoskeleton and activate signaling pathways. We seek to identify key proteins in integrin activation and signaling, structurally and biochemically characterize their interactions, and understand their functional significance in cell adhesion, migration and signaling.

For additional information please see our recent reviews:


Filamins are essential, evolutionarily conserved, actin-binding proteins that organize the actin cytoskeleton and maintain extracellular matrix connections by anchoring actin filaments to transmembrane receptors such as integrins. We have characterized filamin interactions with integrins and their roles in cell migration and adhesion signaling. However, filamins interact with more than 90 other binding partners and so participate in an array of cellular functions. Our recent data implicate filamins in cell differentiation and, consistent with their involvement in a host of biological processes and their many binding partners, filamin mutations cause a variety of human diseases, ranging from altered neuronal migration, to cardiac and skeletal muscle defects, and a spectrum of congenital malformations. In addition, reduced filamin levels correlate with increased breast cancer invasion and metastasis and we discovered that loss of filamin increases extracellular matrix remodeling and cell invasion. Our current work focuses on how filamins influence cell differentiation and extracellular matrix remodeling, and how filamin mutations cause disease.

For additional information please see our recent review:

Cerebral Cavernous Malformations

Loss-of-function mutations in genes encoding KRIT1 (also known as CCM1), CCM2 or PDCD10 (also known as CCM3) cause cerebral cavernous malformations (CCMs). These abnormalities are characterized by dilated leaky blood vessels, especially in the neurovasculature, that result in increased risk of stroke, focal neurological defects and seizures. The three CCM proteins can exist in a trimeric complex, and each of these essential multi-domain adaptor proteins also interacts with a range of signaling, cytoskeletal and adaptor proteins, presumably accounting for their roles in a range of basic cellular processes including cell adhesion, migration, polarity and apoptosis. In collaboration with the Boggon lab (Pharmacology Yale) we have shown that KRIT1 modulates integrin activation by sequestering the integrin inhibitor ICAP1 and we are currently continuing structure function analyses of the CCM interaction network.

For additional information please see our recent review: