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Edward F. Plow, Ph.D.Department ChairThe Robert C. Tarazi, M.D., Endowed Chair in Heart and Hypertension Research
Department of Molecular Cardiology
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Cell adhesion and migration, integrins, platelets, protease receptors, plasminogen, fibronection.
Integrins are a large and broadly distributed family of adhesion receptors. Each member is a noncovalent heterodimer composed of an alpha and a beta subunit.
Key to the many functions of integrins is their capacity to rapidly modulate their affinity for ligands, recognize multiple and structurally unrelated ligands, engage these ligands in a divalent ion-dependent manner, and mediate intracellular signaling events.
Development of a molecular understanding of these central properties of integrins is a goal. Integrins of particular interest are αIIbβ3, which mediates platelet aggregation, and αMβ2, which plays a pivotal role in leukocyte transmigration during inflammatory responses. Mutagenesis, expression, biophysical, immunochemical and functional analyses are being employed in these studies.
Plasminogen is the zymogen form of the proteolytic enzyme plasmin. In addition to its central role in fibrinolysis, plasmin(ogen) is also involved in cell migration. This is evident from the reduction in inflammatory responses to a variety of stimuli in plasminogen-deficient mice. The participation of plasminogen in inflammation depends upon its interaction with cell surface receptors.
We are seeking to identify the repertoire of plasminogen receptors and to assess their functions in vitro and in vivo.
Malinin NL, Zhang L., Choi, J., Ciocea, A., Razorenova, O., Ma, Y-Q., Podrez, E.A., Tosi, M., Lennon D.P., Caplan, A.I., Shurin S.B., Plow, E.F., Byzova T.V., A point mutation in kindlin-3 ablates activation of three integrin subfamilies in humans. Nat. Med., 15:313-318, 2009. PMID: 19234460
Das, R., Burke, T., Van Wagoner, D.R., Plow, E.F. L-Type Calcium Channel Blockers Exert an Antiinflammatory Effect by Suppressing Expression of Plasminogen Receptors on Macrophages. Circ Res 2009;105:167-75. Epub. PMID: 19520970
Malinin, N.L., L. Zhang, J. Choi, A. Ciocea, O.V. Razorenova, Y. Ma, E.A. Podrez, M. Tosi, D.P. Lennon, A.I. Caplan, S.B. Shurin, E.F. Plow, T.V. Byzova. “A point mutation in KINDLIN-3 ablates activation of three integrin subfamilies in humans.” Nature Medicine (Feb. 22, 2009): Epub. PMID: 19234460
Ma YQ, et al. Regulation of integrin αIIbβ3 activation by distinct regions of its cytoplasmic tails. Biochemistry 2006;45:6656-62.
Solovjov DA, Pluskota E, Plow EF. Distinct roles for the alpha and beta subunits in the functions of integrin αMβ2. J Biol Chem 2005;280:1336-45.
Stenina OI, et al. Polymorphisms A387P in thrombospondin-4 and N700S in thrombospondin-1 perturb calcium binding sites. FASEB J 2005;19:1893-5.
Pluskota E, et al. Mechanism and effect of thrombospondin-4 polymorphisms on neutrophil function. Blood 2005;106:3970-8.