Debra K Newman, PhD
Associate Investigator
Blood Research Institute
Blood Center of Wisconsin
Assistant Professor
Department of Pharmacology
Medical College of Wisconsin
Marquette University (1989)
PhD, Physiology and Biophysics
Cardiovascular Pharmacology
Phone: 414 937-3820
Fax: 414-937-6284
debra.newman@bcw.edu
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Research Interests
We study the structure and function of Platelet Endothelial Cell Adhesion Molecule (PECAM)-1, also designated CD31. PECAM-1 is a 130 kDa member of the immunoglobulin (Ig) gene superfamily that is expressed on the surfaces of cells found within the vasculature, including the endothelial cells that line blood vessels and the leukocytes (monocytes, neutrophils and certain T-cell subsets) and platelets that circulate within them. PECAM-1 serves a number of different functions on these cells. Specifically, PECAM-1 is capable of activating integrins, thereby enabling the cells on which PECAM-1 is expressed to adhere better to integrin ligands, which may play a role in leukocyte transmigration from the blood, across the endothelial cell barrier, and into tissues, which usually occurs at sites of inflammation. PECAM-1 also controls the ability of endothelial cells to appropriately respond to the shear stresses of flowing blood. Finally, PECAM-1 functions as an inhibitory receptor that inhibits protein tyrosine kinase (PTK)-dependent signal transduction pathways.
Work in my laboratory is focused on defining the structural foundations for the various functions of PECAM-1. Specifically, we seek to understand how post-translational modifications of the PECAM-1 cytoplasmic domain contribute to its individual functions. Thus far, the best characterized structure-function relationship is between PECAM-1 tyrosine phosphorylation and its inhibitory function. Work in our laboratory as well as that done by others has shown that the cytoplasmic domain of PECAM-1 contains four (mouse) or five (human) tyrosine residues, two of which (positions 663 and 686), become phosphorylated in response to numerous stimuli. When phosphorylated, these two tyrosine residues and the amino acid sequences surrounding them support the binding and activation of an SH2 domain-containing protein tyrosine Phosphatase, SHP-2. We seek to expand upon this knowledge by defining the conditions required for PECAM-1 tyrosine phosphorylation at positions 663 and 686 and the extent to which other post-translational modifications that occur within the PECAM-1 cytoplasmic domain (serine phosphorylation, tyrosine nitration) affect its ability to become tyrosine-phosphorylated and bind SHP-2. Furthermore, PECAM-1 tyrosine phosphorylation and SHP-2 binding is associated with inhibition of PTK-dependent signal transduction by the T cell receptor in T cells, the B cell receptor in B cells and the GPVI collagen receptor in platelets. Studies in PECAM-1-deficient mice have revealed that the absence of this important inhibitory receptor gives rise to B cell and platelet hyperactivity, with an increased propensity for development of autoimmune or thrombotic diseases, respectively. Ongoing studies in our laboratory seek to define the mechanism by which PECAM-1 recruitment of SHP-2 regulates PTK-dependent signal transduction specifically in platelets. Our hope is to ultimately use this information to identify ways to manipulate these pathways and thereby control disease states that are due to defects in platelet function, such as bleeding and thrombosis.
Endothelial cells that line blood vessels are an important source of nitric oxide (NO), which contributes to vessel dilation in response to increases in blood flow and interferes with processes that can lead to development of atherosclerotic plaques in the vasculature. Recent work in our laboratory and that of others has shown that PECAM-1 regulates NO production by endothelial cells. We are currently working to understand how PECAM-1 regulates NO production by endothelial cells, and seek to determine whether PECAM-1 deficiency is a risk factor for development of atherosclerosis.
Selected Publications
Patil, S., D.K. Newman and P.J. Newman. 2001. PECAM-1 serves as an inhibitory receptor that modulates platelet responses to collagen. Blood 97:1727-32.
Newman, D.K., C. Hamilton, M.J. Armstrong and P.J. Newman. 2001. Inhibition of antigen-receptor signaling by platelet endothelial cell adhesion molecule-1 (CD31) requires an intact ITIM, SHP-2, and p56lck. Blood 97:2351-7.
Newman, D.K., S. Hoffman, T. Zhao, S. Kotamraju, B. Wakim, B. Kalyanaraman, and P.J. Newman. 2002. Nitration of ITIM tyrosines abrogates phosphorylation and ability to bind SHP-2. Biochemical and Biophysical Research Communications 296:1171-9.
Gao, C., W. Sun, M. Christofidou-Solomidou, M. Sawada, D.K. Newman, C. Bergom, S.M. Albelda, S. Matsuyama and P.J. Newman. 2003. PECAM-1 functions as a specific and potent inhibitor of mitochondrial apoptosis. Blood 102:169-79.
Newman, P.J. and D.K. Newman. 2003. Signal transduction pathways mediated by PECAM-1: New roles for an old molecule in platelet and vascular biology. Arteriosclerosis, Thrombosis and Vascular Biology 23:953-64.
Rathore, V., M.A. Stapleton, C.A. Hillery, R.R. Montgomery, T.C. Nichols, E.P. Merricks, D.K. Newman and P.J. Newman. 2003. PECAM-1 negatively regulates GPIb/V/IX signaling in murine platelets. Blood 102:3658-64.
Maas, M., R. Wang, C. Paddock, P.J. Newman and D.K. Newman. 2003. Reactive oxygen species induce reversible PECAM-1 tyrosine phosphorylation and SHP-2 binding. American Journal of Physiology: Heart and Circulatory Physiology 285: H2336–H2344.
Boylan, B., H. Chen, V. Rathore, C. Paddock, M. Salacz, K.D. Friedman, B.R. Curtis, M. Stapleton, D.K. Newman, M.L. Kahn and P.J. Newman. 2004. Anti-GPVI-associated ITP: An acquired platelet disorder caused by autoantibody-mediated clearance of the GPVI/FCRg-chain complex from the human platelet surface. Blood 104:1350-5.
Rathore, V., D. Wang, D.K. Newman and P.J. Newman. 2004. Phospholipase Cg2 contributes to stable thrombus formation on VWF. FEBS Letters 573:26-30.
Maas, M., M. Stapleton, C. Bergom, D.L. Mattson, D.K. Newman and P.J. Newman. 2005. Endothelial cell PECAM-1 confers protection against endotoxic shock. American Journal of Physiology: Heart and Circulatory Physiology 288:H159-64.
Falati, S., S. Patil, P.L. Gross, M. Stapleton, G. Merrill-Skoloff, N.E. Barrett, K.L. Pixton, H. Weiler, B. Cooley, D.K. Newman, P.J. Newman, B.C Furie, B. Furie, and J.M. Gibbins. 2006. Platelet PECAM-1 inhibits thrombus formation in vivo. Blood 107:535-541.
Liu, Y., A.B. Bubolz, Y. Shi, P.J. Newman, D.K. Newman, and D.D. Gutterman. 2006. Peroxynitrite reduces the endothelium derived hyperpolarizing factor component of coronary flow-mediated dilation in PECAM-1-knock out mice. American Journal of Physiology: Heart and Circulatory Physiology 290:R57-65.
Rathore, V.B., P.J. Newman and D.K. Newman. 2007. Paxillin family members function as Csk binding proteins that regulate Lyn activity in human and murine platelets. Biochemical Journal 403:275-81.
Machida, K., C.M. Thompson, K. Dierck, K. Jablonowski, S. Karkkainen, B. Liu, H. Zhang, P.D. Nash, D.K. Newman, P. Nollau, T. Pawson, G.H. Renkema, K. Saksela, M. Schiller, D.-G. Shin and B.J. Mayer. 2007. High-throughput phosphotyrosine profiling using SH2 domains. Molecular Cell 26:899-915.
Goel, R., B. Boylan, L. Gruman, P.J. Newman, P. North and D.K. Newman. 2007. The proinflammatory phenotype of PECAM-1-deficient mice results in atherogenic diet-induced steatohepatitis. American Journal of Physiology: Gastrointestinal and Liver Physiology 293(6):G1205-14.