News and Publications

Regulation of Cell Behavior by Integrins

A.J. Pelletier

My laboratory studies the regulation of and signaling by the integrin family of receptors and their ligands. Integrins are heterodimeric, transmembrane receptors that provide adhesion to the extracellular matrix and to other cells. In addition, they mediate both mechanical and biochemical signals that regulate cell behavior. Some, if not all, integrins are conformationally complex molecules; that is, a single integrin can be found in different conformational states, often called activation states. These states have different binding behaviors with their ligands.

My colleagues and I have established that the effect of these different conformers on integrin function is broader than previously known. For example, the integrin _vß₃ exists in at least 2 activation states: activated and basal. In addition to having different ligand-binding properties, the different states mediate different signals and result in different cell behaviors when ligated. Cells may express the different activation states concomitantly; changes in integrin activation states are regulated by cells and correlate with functional changes in cells. Because the basal and activated states interact differentially with the extracellular matrix and can signal differently, a single type of integrin has the potential to detect, and allow cells to respond to, subtle variations in the matrix. This conformation-sensitive signaling is a potential new model for signaling receptors.

Our current work centers on characterizing better the functional distinctions between the activated and basal states, determining the structural bases that underlie the regulation of these states, and understanding the biological role of activation state--specific signaling. We found that activation of _vß₃ involves displacement of a calcium ion from the so-called inhibitory calcium-binding site of the receptor.

Our evidence suggests that integrins in different activation states associate with different cell-surface and intracellular proteins, either directly or as part of larger complexes. Because integrins signal via association with other proteins, this observation provides both support and a possible mechanistic explanation for our model that different activation states signal differently to cells. We have detected several proteins that associate specifically with the activated state of ß₃ integrins, including intracellular kinases, particularly of the Erk family.

In a separate project, we are studying the role of chemokines in regulating migration of T cells and T-cell lines. Specifically, we are exploring the role of the extracellular matrix and integrins in modulating this critical step in immune cell function.

PUBLICATIONS

Domanico, S.Z., Pelletier, A.J., Quaranta, V. Integrin ₆ß₁ stimulates CD81-dependent cell motility without engaging the extracellular matrix migration substrate. Mol. Biol. Cell 8:2253, 1997.

Faccio, R., Grano, M., Colucci, S., Zambonin Zallone, A., Quaranta, V., Pelletier, A.J. Activation of _vß₃ integrin on human osteoclast-like cells simtulates adhesion and migration in response to osteopontin. Biochem. Biophys. Res. Commun., in press.