RESEARCH PROGRAMS AND AFFILIATIONS
Integrin Regulation of the Leukocyte Inflammatory Phenotype
Integrins are the cellular receptors for the proteins which constitute the extracellular matrix of all tissues. The binding of integrin receptors to extraceullular proteins permits cell adhesion and migration during development, wound healing, and inflammation. White blood cells, or leukocytes, are extremely dependent upon integrin receptor recognition of matrix proteins in order to exit the vasculature and resolve inflammatory events within the tissues. Recently it has been recognized that integrin receptors not only provide a physical link between cells and substrates, but also transduce signals to the cell which affect cell behavior.
Our laboratory studies two aspects of leukocyte integrin biology. First, how does the leukocyte utilize these receptors to mediate selective adhesion and migration through complex extracellular tissues? Second, how does the ligation of integrin receptors affect leukocyte behavior? Defining integrin biology at a molecular level, including delineation of required signalling molecules, will produce additional targets for pharmacologic intervention in diseases as diverse as cancers and inflammation.
A recent new direction of the lab is determining control of the actin cytoskeleton. We are testing a new hypothesis that nucleation of cytoskeletal actin originates with the adhesion site - somewhat at odds with currently accepted models. This project has really pushed us into some high tech microscopy approaches that mesh nicely with our cellular, biochemical, and molecular approaches. A new NIH grant, beginning 7/1/04 should push this work along nicely.
The laboratory utilizes techniques ranging from molecular biology to whole animal inflammation models, with an emphasis on cell biology and protein biochemistry. Additional areas of interest include cortical cytoskeleton, signalling paths, cell-cell junctions, infectious pathogens, polarity, metastasis, development, hemostasis and thombosis. While leukocyte behavior remains a major laboratory focus, we also study a variety of vascular and tissue cells, both primary and immortal lines.
Chandhoke, S.K. and Blystone, S.D. Beta-3 integrin phosphorylation is essential for Arp3 organization into leukocyte avb3 -vitronectin adhesions. J. Cell Science, in press for March, 2004.
Blystone, S.D. Kinetic regulation of b3 integrin tyrosine phosphorylation. J. Biol. Chem., 277:49, 46886-46890, 2002.
Butler, D., Williams, M.P., and Blystone, S.D. Ligand-dependent activation of integrin avb3. J. Biol. Chem. ,278:7, 5264-5270, 2003.
Boettiger, D., Huber, F., Lynch, L., and Blystone, S.D. Activation of avb3 -vitronectin binding is a multistage process in which increases in bond strength are dependent on Y747 and Y759 in the Cytoplasmic Domain of b3, Molecular Biology of the Cell , 12:5, p.1227-1237, 2001.
Blystone, S.D., Slater, S.E., Williams, M.P., Crow, M.T., and Brown, E.J. A Molecular Mechanism of Integrin Crosstalk: avß3 Suppression of Calcium/Calmodulin-Dependent Protein Kinase II Regulates a5ß1 Function. J. Cell Biol., 145:889-897, 1999.