Pharmacology and Toxicology

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Debra K. Newman, PhD

Investigator
Blood Research Institute Blood Center of Wisconsin
Associate Adjunct Professor
Department of Pharmacology and Toxicology
Medical College of Wisconsin
Marquette University  (1989)
PhD Immunology
Cardiovascular Pharmacology
Phone: 414 937-3820
Fax: 414-937-6284
debra.newman@bcw.edu

 

Dr. Newman's Faculty Collaboration Database

Research Interests

Activated platelets form thrombi at sites of blood vessel injury that are necessary to control bleeding. If not properly regulated, however, platelets can form pathological thrombi that interfere with the flow of blood to tissues, resulting in ischemia, heart attack, or stroke. To prevent or treat these conditions, it is necessary to better understand the mechanisms that regulate the platelet activation state. Platelets have both activating and inhibitory receptors that send signals into the interior of the cell. It is the balance between these signals that ultimately determines the extent of platelet activation. A major platelet activating receptor is the integrin αIIbβ3, which is required for platelets to form thrombi once they have been activated at sites of vessel injury. Studies in my laboratory are directed at identifying signaling molecules that are utilized uniquely by αIIbβ3 and not by other platelet activating receptors. Such molecules could prove useful as targets to block pathological platelet thrombus formation, while enabling sufficient platelet activation to control bleeding at sites of vessel injury. An important platelet inhibitory receptor is Platelet Endothelial Cell Adhesion Molecule (PECAM)-1, also designated CD31. PECAM-1 is an Immunoglobulin (Ig) domain and Immunoreceptor Tyrosine-based Inhibitory Motif (ITIM)-containing inhibitory receptor that is expressed on the surfaces of platelets, leukocytes (monocytes, neutrophils and certain T-cell subsets), and endothelial cells. Studies in PECAM-1-deficient mice have revealed that, in the absence of this inhibitory receptor, platelets and leukocytes are hyper-responsive which results in an increased propensity for development of cardiovascular and inflammatory diseases, including septic shock, non-alcoholic steatohepatitis and atherosclerosis. The best-characterized mechanism by which PECAM-1 mediates its inhibitory function involves phosphorylation of its two ITIM tyrosine residues, which supports the binding and activation of an SH2 domain-containing protein tyrosine Phosphatase, SHP-2. Current studies in my laboratory are directed at defining how PECAM-1 ITIM phosphorylation is regulated. Specifically, we aim to identify and characterize the enzymes responsible for phosphorylation of each of the ITIMs and to define the events that control access of the ITIMs to the kinases that phosphorylate them. We also seek to determine whether the mechanisms that regulate PECAM-1 ITIM phosphorylate generalize to other dual ITIM-containing inhibitory receptors expressed on platelets and leukocytes. Our hope is to ultimately use this information to identify ways novel ways to control disease complications that result from platelet and leukocyte hyper-responsiveness.


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.

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. 8:1584-93.

Privratsky, J.R., D. K. Newman, and P.J. Newman. PECAM-1: Conflicts of interest in inflammation. Life Sciences 87:69-82.

Keane, C., H. Peterson, Reynolds, K., D.K. Newman, D. Cox, H.F. Jenkinson, P.J. Newman and S.W. Kerrigan. 2010. Contribution of outside-in αIIbβ3-mediated activation of human platelets by the colonizing bacterium, Streptococcus gordonii, to the thrombotic complications of infective endocarditis. Arterioscler. Thromb. Vasc. Biol. 30:2408-15.

Moraes, L.A., L.M. Holbrook, C.I. Jones, N.E. Barrett, M. Spyridon, T. Sage, D.K. Newman, and J.M. Gibbins. 2010. PECAM-1 regulates platelet function through the modulation of the GAB1-SHP-2-PI3-kinase signalling complex. J. Thromb. Haemost. 8:2530-41.

McCormick, M.E., R. Goel, D. Fulton, S. Oess, D. Newman, and E. Tzima. 2011. Platelet-Endothelial Cell Adhesion Molecule-1 regulates endothelial NO synthase activity and localization through signal transducers and activators of transcription 3 dependent NOSTRIN expression. Arterioscler. Thromb. Vasc. Biol. 31:643-9.

Ming, Z., Y. Hu, J. Xiang, Polewski, P.J. Newman, and D.K. Newman. 2011. Lyn and PECAM-1: Interdependent inhibitors of platelet responsiveness. Blood 117:3903-6.

Privratsky, J.R., C.M. Paddock, O. Florey, D.K. Newman, W.A. Muller, and P.J. Newman. 2011. Relative contribution of PECAM-1 adhesion and signaling to the maintenance of vascular integrity. J. Cell. Sci. 124:1477-85.

Gao, C., B. Boylan, J. Fang, D.A. Wilcox, D.K. Newman, and P.J. Newman. 2011. Heparin promotes platelet responsiveness by potentiating αIIbβ3-mediated outside-in signaling. Blood 117:4946-52.

Paddock, C., B.L. Lytle, F.C. Peterson, T. Holyst, P.J. Newman, B.F. Volkman, and D.K. Newman. 2011. Residues within a lipid-associated segment of the PECAM-1 cytoplasmic domain are susceptible to inducible, sequential phosphorylation. Blood 117:6012-23.

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

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

D.K. Newman. 2009. The Y's that bind: Negative regulators of Src family kinase activity in platelets. J. Thromb. Haemost. 7 (Suppl 1) 195-9. 

D.K. Newman. 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)

 
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