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Cell-surface interaction: adhesion receptors mediated signalsCell adhesion to the extracellular matrix substratum affects multiple cellular responses that include gene expression. differentiation. cell viability and morphology. Our long term goal is to identify the intracellular signals transduced. and the pathways that are activated. when cells adhere and spread on surfaces. Integrins are a family of dimeric transmembrane receptors that mediate cell binding to extracellular matrix proteins. Platelets are used in our studies to investigate the mechanism by which integrins regulate cell spreading. These studies are important since the arrest of bleeding is dependent on the ability of platelets to aggregate and spread. We have previously shown that platelet adhesion and spreading on fibrinogen correlates with the induction of tyrosine phosphorylation of several proteins. We identified one of these proteins as the ubiquitously expressed cytoskeletal protein. alpha-actinin. We have also found that alpha-actinin is phosphorylated by the focal adhesion kinase. pp125FAK. One of our current interests is to identify the phosphatase that regulates the state of phosphorylation of alpha-actinin. Research effort is also focused on elucidating the role of tyrosine phosphorylation of the actin binding protein vinculin. A second line of investigation in our laboratory is currently focused on the enteric pathogen Shigella which causes dysentery in humans. While rare in Western countries. the number of deaths attributed to Shigella in third world countries exceeds one million per year. The majority of the casualties (>65%) are children under the age of five. Virulent Shigella species trigger a strong inflammatory reaction. Our goal is to develop an understanding of the mechanism by which Shigella targets and affects human inflammatory cells. Selected PublicationsCraig DH, Haimovich B, Basson MD. (2007) Alpha-actinin-1 phosphorylation modulates pressure-induced colon cancer cell adhesion through regulation of focal adhesion kinase-Src interaction. Am J Physiol Cell Physiol. 293(6):C1862-74. Moese S, Selbach M, Brinkmann V, Karlas A, Haimovich B, Backert S, Meyer TF. (2007) The Helicobacter pylori CagA protein disrupts matrix adhesion of gastric epithelial cells by dephosphorylation of vinculin. Cell Microbiol. 9(5):1148-61. Haimovich B. Venkatesan MM. (2006) Shigella and Salmonella: death as a means of survival. Microbes Infect. 8(2):568-77. Zhang Z. Lin SY. Neel BG. Haimovich B. (2006) Phosphorylated alpha-actinin and protein-tyrosine phosphatase 1B coregulate the disassembly of the focal adhesion kinase x Src complex and promote cell migration. J Biol Chem. 281(3):1746-54. Koterski JF. Nahvi M. Venkatesan MM. Haimovich B. (2005) Virulent Shigella flexneri causes damage to mitochondria and triggers necrosis in infected human monocyte-derived macrophages. Infect Immun. 73(1):504-13. Zhang Z. Izaguirre G. Lin SY. Lee HY. Schaefer E. Haimovich B. (2004) The phosphorylation of vinculin on tyrosine residues 100 and 1065. mediated by SRC kinases. affects cell spreading. Mol Biol Cell. 15(9):4234-47. Lin SY. Raval S. Zhang Z. Deverill M. Siminovitch KA. Branch DR. Haimovich B. (2004) The protein-tyrosine phosphatase SHP-1 regulates the phosphorylation of alpha-actinin. J Biol Chem. 279(24):25755-64. von Wichert G. Haimovich B. Feng GS. Sheetz MP. (2003) Force-dependent integrin-cytoskeleton linkage formation requires downregulation of focal complex dynamics by Shp2. EMBO J. 22(19):5023-35. Chang S. Popowich Y. Greco RS. Haimovich B. (2003) Neutrophil survival on biomaterials is determined by surface topography. J Vasc Surg. 37(5):1082-90. Izaguirre. G. Aguirre. L. Hu. Y-A. Young H.Y.. Schlaepfer. D.D.. Aneskievich. B. and Haimovich. B. (2001). The cytoskeletal/non-muscle isoform of alpha-actinin is phosphorylated on its actin-binding domain by the focal adhesion kinase. J. Biol. Chem. 276:28676-28685. |
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