Research Overview: Perturbations in the normal homeostatic mechanisms that regulate the interaction of cells with their surrounding extracellular matrix (ECM) result in a diverse array of pathologies such as cancer and fibrosis. The integrin family of adhesion molecules function as receptors for ECM proteins but, also modulate the activity of cytokines such as TGF-β . Using models based on human tissue, transgenic and knock-out mice, we study the role that specific integrins play in the expression and activity of secreted growth factors and proteases and how these factors effect cell proliferation, migration and ECM deposition. We envision that these studies will provide a mechanistic basis of understanding of the human diseases that we focus on, pulmonary fibrosis, cancer and vascular malformations. In addition, we are investigating the structural basis of integrin-ligand interactions using a system that we have developed where we are able to “trap” various integrin conformational states to observe differences in receptor affinity and ligand recognition. These studies suggest that different integrin conformations show binding preference for distinct ligands. The ultimate goal of these studies is to develop specific therapeutics that selectively inhibit pathologic integrin functions while not effecting required integrin function.

Cambier, Stephanie, Mu, De-zhi, O' Connell, D., Boylen, K., Travis, W., Liu, W.,. Broaddus, V C, Nishimura, S. L . A role foe the divergent integrin αvβ8 in negative regulation of epithelial cell growth Cancer Res, 2000 Dec 15;60(24):7084-93

Mu, Dezhi, Cambier, S, Baron, JL, Munger, J, Sheppard, D, Broaddus, VC, Nishimura, SL , The integrin αvβ58 mediates epithelial homeostasis through the MT1-MMP-dependent activation of TGFβ . J Cell Biol, 2002, Apr 29;157(3):493-507.

Jarad, G., Wang, B., Khan, S., DeVore, J., Miao, H., Wu, K., Nishimura, S.L., Wible, B.A., Konieczkowski, M., Sedor, J.R., Schelling, J.R., Fas Activation Induces Renal Tubular Epithelial Cell β8 Integrin Expression and Function in the Absence of Apoptosis, J Biol Chem. 2002 Dec 6;277(49):47826-47833

Fjellbirkeland, L., Cambier, S., Dolganov, G., Hill, A., Brunetta, P., Jablons, D., Ten Dijke, P., Nishimura, S.L., Integrin-mediated activation of TGFβ inhibits human airway epithelial proliferation in situ, Am. J. Path., 2003, 163(2) 533-542

Jackson T, Clark S, Berryman S, Burman A, Cambier S, Mu D, Nishimura S , King AM. Integrin αvβ8 functions as a receptor for foot-and-mouth disease virus: role of the beta-chain cytodomain in integrin-mediated infection. J Virol. 2004 May;78(9):4533-4

Gline, S.E., Cambier, S., Govaerts, C., Nishimura, S.L., A 50 A separation of the integrin αvβ3 extracellular domain C-termini reveals an intermediate activation state J Biol Chem 2004, 279: 54567-54572

Cambier, S., Gline, S.E., Araya, J, Collins, R., Einheber, S., Dolganov, G., Boudreau, N., Nishimura, S.L ., Integrin αvβ8-mediated activation of TGFβ: an angiogenic control switch, Am. J. Path., 2005, 166 (6): 1883-1893