Research Interests
Central to the ability of vascular cells to adhere to the extracellular matrix 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 (often referred to an outside/in and inside/out signal transduction, respectively). Such post-ligand events occur by virtue of the ability of these transmembrane proteins to interact with intracellular kinases and phosphatases, G-proteins, adapter proteins, and cytoskeletal components. Our laboratory divides its attention between exploring the role of stimulatory and inhibitory receptors in regulating adhesion and aggregation of human and murine platelets (funded through a Program Project grant), redox signaling in endothelial cells (funded through a different Program Project Grant with the Medical College of Wisconsin), and the structure and function of PECAM-1 in the blood and vascular cells in which it is expressed (funded through a long-standing R01).
Current Grant Support
NIH Grant R01 HL40926, years 18-21 Molecular Biology and Function of PECAM-1
NIH Training Grant HL-07209 (Co-PI with R.H. Aster)
NIH Program Project PO1-HL68769 (Vascular Cell Signaling, Leader, Project 3) – Endothelial Redox Signaling Mediated by PECAM-1
NIH Program Project Grant P01-HL44612, years 16-20 (Program Director, Leader, Project 1, and Director of Administrative Core A) – Molecular Mechanisms of Platelet Activation and Adhesion
Ongoing NIH-funded research projects are listed below:
Gene expression analysis using DNA microarrays
Adhesive and signaling properties of PECAM-1-deficient murine blood and vascular cells
Regulation of the GVI/FcR gamma-chain complex in human and murine platelets
Role of serine phosphorylation in PECAM-1 inhibitory signaling
Construction of transgenic and knock-in mice with altered adhesive and signaling properties
Determining using 2-D NMR the solution structure of the PECAM-1 cytoplasmic domain.
Characterizing mechanisms involved in PECAM-1-mediated cytoprotection
Identification of the molecular mechanisms by which PECAM-1 affects endothelial cell permeability in response to cytokine activation.
Elucidating the molecular mechanism by which anti-GPVI antibodies remove the GPVI/FcRg chain complex from the platelet surface for the treatment of myocardial infarction and stroke
Determine the mechanism by which PECAM-1 via its ability to recruit SHP-2, negatively regulates activation of Src family kinases
Determine whether PECAM-1 expression varies in the human population, and whether variable PECAM-1 expression might predispose individuals to arterial thrombosis or hemorrhage.
Recent Publications
Sun J, Paddock C, Shubert J, Zhang H, Amin K, Newman PJ, and Albelda SM: Contributions of the extracellular and cytoplasmic domains of Platelet Endothelial Cell Adhesion Molecule-1 (PECAM-1/CD31) in regulating cell-cell localization. J Cell Sci. 113:1459-1469, 2000.
Ward CM, Weyerbusch-Bottum S, Kestin AS, and Newman PJ: A Leu262Pro mutation in the integrin beta(3) subunit results in an alpha(IIb-beta(3) complex that binds fibrin but not fibrinogen. Blood 96:161-169, 2000.
Mahooti S, D Graesser, S Patil, PJ Newman, G Duncan, T Mak and JA Madri: PECAM-1 (CD31) expression modulated bleeding time in vivo. Am J Path 157:75-81, 2001.
Zhao T and PJ Newman: Integrin activation by regulated dimerization and oligomerization of PECAM-1 from within the cell. J Cell Biol 152:65-73, 2001.
Patil S, DK Newman, and PJ Newman: PECAM-1 serves as an inhibitory receptor that modulates platelet responses to collagen. Blood 97:1727-1732, 2001.
French DL, PJ Newman, and M Poncz: Inherited disorders of platelets. In The Metabolic and Molecular Bases of Inherited Disease, Eighth Edition, Volumes I-IV, (CR Scriver, AL Beaudet, D Valle, and WS Sly, eds.) McGraw Hill Publishing Company, pp. 4473-4504, 2001.
Newman DK, C Hamilton, and PJ Newman: Inhibition of antigen-receptor signaling by Platelet Endothelial Cell Adhesion Molecule- 1 (CD31) requires an intact ITIM, SHP-2, and p56lck. Blood 97: 2351-2357, 2001.
C. Ruiz, CY Liu, QH. Sun, M Sigaud-Fiks, E Fressinaud, JY Muller, P Nurden, A T Nurden, PJ Newman, and N Valentin: A point mutation in the cysteine-rich domain of glycoprotein (GP) IIIa results in the expression of a GPIIb-IIIa (aIIbB3) integrin receptor locked in a high-affinity state and a Glanzmann thrombasthenia-like phenotype. Blood 98: 2432-2441, 2001.
Newman DK, S Hoffman, S Kotamraju, T Zhao, B Wakim, B Kalyanaraman, and PJ Newman: Nitration of PECAM-1 ITIM tyrosines abrogates phosphorylation and SHP-2 binding. Biochemical and Biophysical Research Communications 296:1171-1179, 2002.
Sun Q-H, C-Y Liu, R Wang, C Paddock, and PJ Newman: Disruption of the long-range GPIIIa Cys5-Cys435 disulfide bond results in the production of a constitutively active GPIIb-IIIa (aIIbB3) integrin complex. Blood 100:2094-2101, 2002.
Gao C, W Sun, M Christofidou-Solomidou, M Sawada, DK Newman, C Bergom, SM Albelda, S Matsuyama, and PJ Newman: PECAM-1 functions as a specific and potent inhibitor of mitochondrial-dependent apoptosis. Blood 102:169-179, 2003.
Newman PJ, JG McFarland, and RH Aster: Alloimmune Thrombocytopenias. In Thrombosis and Hemorrhage, 3rd Edition, (J. Loscalzo, A. I. Schafer, eds.) Lippincott Williams and Wilkins, Philadelphia, PA., pp. 441-456, 2003.
Rathore V, MA Stapleton, CA Hillery, RR Montgomery, TC Nichols, EP Merricks, DK Newman, and PJ Newman: PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets. Blood 102:3658-3664, 2003.
Newman PJ and DK Newman: Signal transduction pathways mediated by PECAM-1: New roles for an old molecule in platelet and vascular biology. Atheroscler Thromb Vasc Biol 23: 953-964, 2003.
Maas M, R Wang, C Paddock, S Kotamraju, B Kalyanaraman, PJ Newman, DK Newman: Reactive oxygen species induce reversible PECAM-1 tyrosine phosphorylation and SHP-2 binding. Am J Physiol Heart Circ Physiol 285:H2336-H2344, 2003.
Boylan, B, H Chen, V Rathore, C Paddock, M Salacz, KD Friedman, BR Curtis, M Stapleton, DK Newman, and PJ Newman: Anti-GPVI-associated ITP: An acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FcRy-chain complex from the human platelet surface. Blood 104:1350-1355, 2004.
Shattil SJ and PJ Newman: Integrins: Dynamic scaffolds for adhesion and signaling in platelets. Blood 104:1606-1615, 2004.
Rathore V, D Wang, DK Newman and PJ Newman: Phospholipase Cã2 contributes to stable thrombus formation on VWF. FEBS Letters 573:26-30, 2004.
Maas M, MA Stapleton, CR Bergom, DL Mattson, DK Newman, and PJ Newman: Endothelial PECAM-1 confers protection against endotoxic shock. Am J Physiol Heart Circ Physiol 288:H159-H164, 2005.