Debra K. Newman, Ph.D.

Investigator

Blood Research Institute
BloodCenter of Wisconsin

Assistant Professor

Department of Pharmacology & Toxicology
and Microbiology
Medical College of Wisconsin

Doctoral Training

Ph.D., Marquette University, 1989

Selected Publications
Grant Support
Laboratory Staff
Contact Information

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 mechanisms underlying 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 (e.g., serine phosphorylation) 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 cellular hyper-responsiveness and an increased propensity for development of inflammatory diseases, including septic shock, non-alcoholic steatohepatitis and atherosclerosis. Ongoing studies in our laboratory seek to define the mechanisms by which PECAM-1 becomes phosphorylated, recruits SHP-2 and/or other binding partners, and regulates the cellular activation state. Our hope is to ultimately use this information to identify ways to manipulate these pathways and thereby control inflammatory diseases or those that are due to defects in platelet and immune cell functions, such as bleeding, thrombosis, and inflammation.

Grant Support

NIH, R01 HL090883, "Negative Regulation of Platelet Activity" (2008-2011)

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 p56^lck. 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/FCRγ-chain complex from the human platelet surface. Blood 104:1350-5.
• Rathore, V., D. Wang, D.K. Newman and P.J. Newman. 2004. Phospholipase Cγ2 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:G1205-14.
• Bergom, C., C. Paddock, C. Gao, T. Holyst, D.K. Newman, and P.J. Newman. 2007. An alternatively spliced isoform of PECAM-1 is expressed at high levels in human and murine tissues, and suggests a novel role for the C-terminus of PECAM-1 in cytoprotective signaling. 2008. .J Cell Sci. 121:1235-42.
• Goel, R., B. Schrank, S. Arora, B. Boylan, B. Fleming, H. Miura, P.J. Newman, R.C. Molthen, and D.K. Newman. 2008. PECAM-1 deficiency affects atherosclerosis in LDL receptor-deficient mice in a site-specific manner. Arterioscler. Thromb. Vasc. Biol. 28:1996-2002.
• Boylan, B., C. Gao, V. Rathore, J.C. Gill, D.K. Newman and P.J. Newman. 2008. Identification of FcγRIIa as the ITAM-bearing receptor mediating αIIbβ3 outside-in integrin signaling in human platelets. Blood 112:2780-2786. 
• Gao, C., B. Boylan, D. Bougie, J.C. Gill, J. Birenbaum, D.K. Newman, R.H. Aster and P.J. Newman. 2009. Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcγRIIa and the integrin β3 cytoplasmic domain. J. Clin. Invest. 113:504-11. 
• Newman, D.K. 2009. The Y's that bind: Negative regulators of Src family kinase activity in platelets. J. Thromb. Haemost. 7 (Suppl 1) 195-9. 
• Newman, D.K. 2009. PI3Kβ goes to the head of its class. Blood 114:2011-2. 
• Privratsky, J.R., B.E. Tourdot, D.K. Newman and P.J. Newman. 2010. The anti-inflammatory actions of PECAM-1 do not involve regulation of endothelial cell NF-κB. J. Immunol. 184:3157-63. 
• Bayat, B., S. Werth, U.J.H. Sachs, D.K. Newman, P.J. Newman, and S. Santoso. 2010. Neutrophil transmigration mediated by the neutrophil-specific antigen CD177 is influenced by the endothelial S₅₃₆N dimorphism of PECAM-1. J. Immunol. 184:3889-93. 
• Fornasa, G., E. Groyer, M. Clement, J. Dimitrov, C. Compain, A.-T. Gaston, A. Varthaman, J. Khallou-Laschet, D. K. Newman, S. Graff-Dubois, A. Nicoletti, and G. Caligiuri. 2010. TCR stimulation drives cleavage and shedding of the ITIM-receptor CD31. J. Immunol. 184:5485-92. 
• Crockett, J., D.K. Newman, and P.J. Newman. PECAM-1 is a negative regulatory of laminin-induced platelet activation. J. Thromb. Haemost. (In press). 
• Privratsky, J.R., D. K. Newman, and P.J. Newman. PECAM-1: Conflicts of interest in inflammation. Life Sciences (In Press).
   

Laboratory Staff
 

From left: Deb Newman (Investigator), Deb Schaller (Admin Asst), Maya Bates (Undergraduate Student), Michelle Brenner (Research Technologist), Marge Kipp (Animal Technologist), Ben Tourdot (Graduate Student), Chris Kuckelburg (Postdoctoral Fellow), Cathy Paddock (Sr. Research Technologist), Jimmy Crockett (Postdoctoral Fellow), Peter Newman (Sr. Investigator), Ben Andrew (Research Technologist), Taisuke Kanaji (Research Scientist). Missing: Cunji Gao (Research Scientist)

Employment Opportunities
If opportunities are available, they will be listed on the Employment page.

Contact Information
Phone: (414) 937-3820
Fax: (414) 937-6284
E-mail: debra.newman@bcw.edu