Salvatore Pizzo, MD, PhD

Chair

Department / Division:
Pathology / Pathology

Address:
DUMC 3712
Durham, NC 27710

Office Telephone:
919-684-3528

Fax Telephone:
919-684-8689

• MD, Duke University School of Medicine, 1973

• Pathology, Duke University Medical Center, 1973-1976
• Medicine, Duke University Medical Center, 1976-1979

• PhD, Duke University, 1973

Clinical Interests:
Coagulation, biochemistry, serum and electrophoresis, immunoelectrophoresis

Research Interests:
RESEARCH ABSTRACT
The laboratory pursues a number of projects in which proteolytic events play major roles in cell biology.  This includes angiogenesis, regulation of cellular growth, and immune regulation.  Folkman and colleagues demonstrated angiostatin, a proteolytic fragment of plasminogen/plasmin, inhibits endothelial cell growth thus causing the death of tumors.  In 1999, we first identified cell surface-associated ATP synthase as the angiostatin receptor.  Subsequently, we demonstrated that the molecule is fully functional, generating ATP on the external plasma membrane leaflet.  Angiostatin binds to the catalytic β-subunit of the synthase inhibiting ATP synthesis and also the translocation of H+ in the direction of ATP synthesis.  This is of little consequence to endothelial cells at neutral pH; however, at low pH which is typical of the tumor microenvironment, the inability of H+ to move out of the cell causes the internal pH of these cells to fall to 6.5 and the endothelial cells then die.  Recently, we have shown that ATP synthase is also on the surface of a number of tumor cells and angiostatin kills these cells directly by the same mechanism at low environmental pH.  We have also shown that antibodies targeting the catalytic β-subunit of the synthase are angiostatin-mimetics.  In addition a group of stillbenes found in grapes, hence red wine, by directly inhibiting the synthase in part explains the reported beneficial effects of red wines/grape juice.

Studies of proteinase regulation by the plasma protein α2-macroglobulin (α2M) led us to the discovery of a cell surface receptor which when activated regulates cell growth. We identified this receptor as cell surface-associated GRP78 in 2002.  This is an observation as surprising as finding ATP synthase on the cell surface since GRP78 is normally an ER protein. Over the last several years we and others have demonstrated that the occurrence of GRP78 on the surface of human prostate cancer is a very poor prognostic marker. In such patients, an autoantibody directed against GRP78 is a better marker than PSA as a predictor of a highly metastatic tumor.  We have extensively characterized the receptor biology of activated α2M (α2M*) ligation of cell surface GRP78. This event occurs with high affinity (Kd ~50 pM) and is both progrowth and antiapoptotic.

Finally, we have demonstrated that when activated by proteolysis or an alternative chemistry discovered in our laboratory, α2M* is a carrier of antigens via a second receptor LRP, into dendritic cells/macrophages.  This results in a marked augmentation of both MHC Class I and II antigen presentation mechanisms.

Representative Publications:
Wahl ML, Moser TL, Pizzo SV. Angiostatin and Anti-angiogenic Therapy in Human Disease. Recent Prog Horm Res. 2004;59:73-104. (2004) Abstract

Misra UK, Pizzo SV. Potentiation of signal transduction mitogenesis and cellular proliferation upon binding of receptor-recognized forms of alpha2-macroglobulin to 1-LN prostate cancer cells. Cell Signal. 2004 Apr;16(4):487-96. (2004) Abstract

Hart JP, Gunn MD, Pizzo SV. A CD91-positive subset of CD11c+ blood dendritic cells: characterization of the APC that functions to enhance adaptive immune responses against CD91-targeted antigens. J Immunol. 2004 Jan 1;172(1):70-8. (2004) Abstract

Misra UK, Gawdi G, Pizzo SV. Induction of mitogenic signalling in the 1LN prostate cell line on exposure to submicromolar concentrations of cadmium(+). Cell Signal. 2003 Nov;15(11):1059-70. (2003) Abstract

McLachlan JB, Hart JP, Pizzo SV, Shelburne CP, Staats HF, Gunn MD, Abraham SN. Mast cell-derived tumor necrosis factor induces hypertrophy of draining lymph nodes during infection. Nat Immunol. 2003 Dec;4(12):1199-205. (2003) Abstract

Mathew S, Arandjelovic S, Beyer WF, Gonias SL, Pizzo SV. Characterization of the interaction between alpha2-macroglobulin and fibroblast growth factor-2: the role of hydrophobic interactions. Biochem J. 2003 Aug 15;374(Pt 1):123-9. (2003) Abstract

Gonzalez-Gronow M, Kalfa T, Johnson CE, Gawdi G, Pizzo SV. The voltage-dependent anion channel is a receptor for plasminogen kringle 5 on human endothelial cells. J Biol Chem. 2003 Jul 18;278(29):27312-8. (2003) Abstract

Fields RC, Schoenecker JG, Hart JP, Hoffman MR, Pizzo SV, Lawson JH. Protease-activated receptor-2 signaling triggers dendritic cell development. Am J Pathol. 2003 Jun;162(6):1817-22. (2003) Abstract

Berwin B, Hart JP, Rice S, Gass C, Pizzo SV, Post SR, Nicchitta CV. Scavenger receptor-A mediates gp96/GRP94 and calreticulin internalization by antigen-presenting cells. EMBO J. 2003 Nov 17;22(22):6127-36. (2003) Abstract

Misra UK, Gawdi G, Akabani G, Pizzo SV. Cadmium-induced DNA synthesis and cell proliferation in macrophages: the role of intracellular calcium and signal transduction mechanisms. Cell Signal. 2002 Apr;14(4):327-40. (2002) Abstract

Misra UK, Akabani G, Pizzo SV. The role of cAMP-dependent signaling in receptor-recognized forms of alpha 2-macroglobulin-induced cellular proliferation. J Biol Chem. 2002 Sep 27;277(39):36509-20. (2002) Abstract

Liao HX, Cianciolo GJ, Staats HF, Scearce RM, Lapple DM, Stauffer SH, Thomasch JR, Pizzo SV, Montefiori DC, Hagen M, Eldridge J, Haynes BF. Increased immunogenicity of HIV envelope subunit complexed with alpha2-macroglobulin when combined with monophosphoryl lipid A and GM-CSF. Vaccine. 2002 May 22;20(17-18):2396-403. (2002) Abstract

Gonzalez-Gronow M, Gawdi G, Pizzo SV. Tissue factor is the receptor for plasminogen type 1 on 1-LN human prostate cancer cells. Blood. 2002 Jun 15;99(12):4562-7. (2002) Abstract

Cuchacovich M, Gatica H, Vial P, Yovanovich J, Pizzo SV, Gonzalez-Gronow M. Streptokinase promotes development of dipeptidyl peptidase IV (CD26) autoantibodies after fibrinolytic therapy in myocardial infarction patients. Clin Diagn Lab Immunol. 2002 Nov;9(6):1253-9. (2002) Abstract

Berwin B, Hart JP, Pizzo SV, Nicchitta CV. Cutting edge: CD91-independent cross-presentation of GRP94(gp96)-associated peptides. J Immunol. 2002 May 1;168(9):4282-6. (2002) Abstract

Misra UK, Gawdi G, Pizzo SV. Potentiation of calcium levels by extracellular arachidonic acid in nuclei isolated from macrophages stimulated with receptor-recognized forms of alpha(2)-macroglobulin. Cell Signal. 2000 Feb;12(2):99-104. (2000) Abstract

Bhattacharjee G, Asplin IR, Wu SM, Gawdi G, Pizzo SV. The conformation-dependent interaction of alpha 2-macroglobulin with vascular endothelial growth factor. A novel mechanism of alpha 2-macroglobulin/growth factor binding. J Biol Chem. 2000 Sep 1;275(35):26806-11. (2000) Abstract

Wu SM, Pizzo SV. Mechanism of hypochlorite-mediated inactivation of proteinase inhibition by alpha 2-macroglobulin. Biochemistry. 1999 Oct 19;38(42):13983-90. (1999) Abstract

Moser TL, Stack MS, Asplin I, Enghild JJ, Højrup P, Everitt L, Hubchak S, Schnaper HW, Pizzo SV. Angiostatin binds ATP synthase on the surface of human endothelial cells. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):2811-6. (1999) Abstract

Misra UK, Gawdi G, Gonzalez-Gronow M, Pizzo SV. Coordinate regulation of the alpha(2)-macroglobulin signaling receptor and the low density lipoprotein receptor-related protein/alpha(2)-macroglobulin receptor by insulin. J Biol Chem. 1999 Sep 3;274(36):25785-91. (1999) Abstract