Central to the ability of vascular cells to adhere to both extracellular matrix components and to each other is an abundant supply of cell surface adhesion molecules that, in addition to influencing the adhesive phenotype of the cell, are also capable of transmitting signals into, and responding to signals from, the cell interior. Such post-ligand events occur by virtue of the ability of these transmembrane proteins to interact with intracellular kinases and phosphatases, G-proteins, and cytoskeletal components. Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1) is a 130 kDa member of the Immunoglobulin (Ig) superfamily that is expressed on the surface of circulating platelets, monocytes, neutrophils, and selected T-cell subsets. It is also a major constituent of the endothelial cell intercellular junction, where up to 1 x 106 PECAM-1 molecules are concentrated. We have recently shown that PECAM- 1 belongs to a newly-described family of Ig-like Inhibitory Receptors, each of which harbors one or more Immunoreceptor Tyrosine-based Inhibitory Motifs (ITIMs) within their cytoplasmic domains. Following cellular activation, the PECAM-1 ITIMs become tyrosine phosphorylated, forming a docking site for the recruitment and activation of the protein tyrosine phosphatase, SHP-2, and perhaps SHP-1. The goal of this competitive renewal application is to build on recent observations regarding the adhesive and signaling properties of PECAM-1, and to continue to explore the function of this receptor in blood and vascular cells. Specifically, over the next five-year period, we propose to (1) test the hypothesis that PECAM-1 monomers, dimers, and oligomers exist within the plane of the plasma membrane, and that controlling the equilibrium among these forms may have profound effects on the adhesive and signaling properties of this receptor; (2) explore the range of cellular targets for PECAM- 1/phosphatase signaling complexes; (3) test the hypothesis that serine phosphorylation of the PECAM-1 cytoplasmic domain serves to uncouple platelet activation from PECAM-1 mediated signal transduction by preventing association of SHP-2 and SHP-1 with PECAM-1; and (4) investigate the relative contribution of platelets and endothelial cells to increased bleeding times recently observed in PECAM-1 deficient mice. Together, these studies comprise a coordinated, focused research program designed to improve our understanding of the function of both the extracellular and cytoplasmic domains of PECAM-1 in the blood and vascular cells in which it is expressed. We expect that information derived from this investigation will lead to improved understanding of the role of this novel cell adhesion and signaling receptor in thrombosis, inflammation, angiogenesis, and the immune response.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL040926-14
Application #
6389068
Study Section
Hematology Subcommittee 2 (HEM)
Program Officer
Ganguly, Pankaj
Project Start
1988-07-01
Project End
2005-06-30
Budget Start
2001-08-10
Budget End
2002-06-30
Support Year
14
Fiscal Year
2001
Total Cost
$361,950
Indirect Cost
Name
Bloodcenter of Wisconsin, Inc.
Department
Type
DUNS #
City
Milwaukee
State
WI
Country
United States
Zip Code
53233
Liao, Danying; Mei, Heng; Hu, Yu et al. (2018) CRISPR-mediated deletion of the PECAM-1 cytoplasmic domain increases receptor lateral mobility and strengthens endothelial cell junctional integrity. Life Sci 193:186-193
Newman, Debra K; Fu, Guoping; McOlash, Laura et al. (2018) Frontline Science: PECAM-1 (CD31) expression in naïve and memory, but not acutely activated, CD8+ T cells. J Leukoc Biol 104:883-893
Paddock, Cathy; Zhou, Dongwen; Lertkiatmongkol, Panida et al. (2016) Structural basis for PECAM-1 homophilic binding. Blood 127:1052-61
Lertkiatmongkol, Panida; Liao, Danying; Mei, Heng et al. (2016) Endothelial functions of platelet/endothelial cell adhesion molecule-1 (CD31). Curr Opin Hematol 23:253-9
Newman, Debra K; Fu, Guoping; Adams, Tamara et al. (2016) The adhesion molecule PECAM-1 enhances the TGF-?-mediated inhibition of T cell function. Sci Signal 9:ra27
Privratsky, Jamie R; Newman, Peter J (2014) PECAM-1: regulator of endothelial junctional integrity. Cell Tissue Res 355:607-19
Mei, Heng; Campbell, Jay M; Paddock, Cathy M et al. (2014) Regulation of endothelial cell barrier function by antibody-driven affinity modulation of platelet endothelial cell adhesion molecule-1 (PECAM-1). J Biol Chem 289:20836-44
Tourdot, Benjamin E; Brenner, Michelle K; Keough, Kathleen C et al. (2013) Immunoreceptor tyrosine-based inhibitory motif (ITIM)-mediated inhibitory signaling is regulated by sequential phosphorylation mediated by distinct nonreceptor tyrosine kinases: a case study involving PECAM-1. Biochemistry 52:2597-608
Kuckleburg, Christopher J; Newman, Peter J (2013) Neutrophil proteinase 3 acts on protease-activated receptor-2 to enhance vascular endothelial cell barrier function. Arterioscler Thromb Vasc Biol 33:275-84
Privratsky, Jamie R; Tilkens, Sarah B; Newman, Debra K et al. (2012) PECAM-1 dampens cytokine levels during LPS-induced endotoxemia by regulating leukocyte trafficking. Life Sci 90:177-84

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