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Molecular Medicine

Faculty

Mary Jo Heeb, Ph.D.

Professor Emeritus
Department of Molecular Medicine
California Campus
Laboratory Website
heeb@scripps.edu
(858) 784-2185

Research Focus

Regulation of Blood Coagulation

We study several anticoagulant proteins with the view that understanding mechanisms by which these proteins regulate blood coagulation may lead to new therapies or preventative measures for thrombotic disease. Protein S is a nonenzymatic vitamin K-dependent protein that acts as a cofactor for activated protein C in the proteolytic inactivation of procoagulant factors Va and VIIIa. We showed that protein S also has direct anticoagulant activity by virtue of binding and inhibition of factors Xa and Va. This activity is demonstrable in plasma and is modulated by several mechanisms that we seek to elucidate, including incorporation of intramolecular zinc into protein S.

We found that knock-out mice that were total deficient in protein S died in utero and were characterized by severe coagulopathy and leaky blood vessels. Mice that were heterozygous protein S-deficient were viable but were underrepresented in the litters. Their plasma was deficient in both activated protein C cofactor activity of protein S and direct protein S anticoagulant activity. In a baboon thrombosis model, protein S was antithrombotic in the absence of activated protein C, demonstrating possible therapeutic potential in treating or preventing thrombosis in humans in the future.

Protein Z is another vitamin K-dependent nonenzymatic protein that serves as a cofactor to a recently discovered serpin, protein Z-dependent protease inhibitor (ZPI). We showed that low protein Z levels are associated with stroke. ZPI is an unusual serpin that inhibits procoagulant factor Xa in a manner dependent on phospholipids, protein Z and calcium ions but not requiring formation of a covalent factor Xa-ZPI complex. We found that ZPI also efficiently and rapidly inhibits procoagulant factor IXa independently of phospholipids and protein Z.

A separate focus involves development of plasma assays for forms of prostate specific antigen and human glandular kallikrein that could aid in distinguishing prostate cancer from benign prostate disease, or that could aid in prognosis of prostate cancer. The aims are to reduce the number of prostate biopsies required (2/3 are negative) and to identify which cases of prostate cancer have a poor prognosis and require aggressive treatment.

Awards & Professional Activities

American Heart Association Established Investigator
Who’s Who listings
Member, American Society of Hematology, American Society for Biochemistry and Molecular Biology, International Society for Thrombosis and Haemostasis
Reviewer for Blood, Journal of Thrombosis and Haemostasis, Thrombosis and Haemostasis,and other journals.

Selected References

Burstyn-Cohen, T., Heeb, M.J., Lemke, G., Lack of protein S in mice causes embryonic lethal coagulopathy and vascular dysgenesis. J. Clin. Invest. 119:2942, 2009.

Heeb, M.J., Prashun, D., Griffin, J.H., Bouma, B.N. Plasma protein S contains zinc essential for efficient activated protein C-independent anticoagulant activity and binding to factor Xa, but not for efficient binding to tissue factor pathway inhibitor. FASEB J., 23:2244-2253, 2009.

Fernández, J.A.*, Heeb, M.J.*, Xu, X., Singh, L., Zlokovic, B.V., Griffin, J.H. Species-specific anticoagulant and mitogenic activities of murine protein S. Hematologica, 94:1721-1731, 2009. * These authors contributed equally.

Heeb, M.J., Ruan, L., Cabral, K., Tonnu, L. Downregulation of factor IXa in the factor Xase complex by protein Z-dependent protease inhibitor. J. Biol. Chem., 280:33819-33925, 2005.

Links

Scientific Report 2008

Molecular Medicine Seminar Series

CA Faculty

Asahara, Hiroshi
Balch, William E.
Boddy, Michael
Buxbaum, Joel
Catz, Sergio
Conti, Bruno
Cravatt, Benjamin
D'Lima, Darryl
DerMardirossian, Celine
Deryugina, Elena
Elias, Darlene
Encalada, Sandra
Felding, Brunhilde
Fowler, Velia
Friedlander, Martin
Gerace, Larry
Gottesfeld, Joel
Griffin, John
Hanneken, Anne
Heeb, Mary Jo
Henderson, Scott
Hoch, James
Joazeiro, Claudio
Johnson, Eric
Kanaji, Taisuke
Kay, Steve
Kelly, Jeffery
Koziol, James
Lamia, Katja
Lazzerini Denchi, Eros
Lipton, Stuart
Loring, Jeanne F.
Loskutoff, David
Lotz, Martin
Makarenkova, Helen P.
Mc Millan, Robert
Miles, Lindsey
Milner, Richard
Modena, Brian
Mosnier, Laurent
Paulson, James C.
Perego, Marta
Petrascheck, Michael
Pollard, Kenneth Michael
Quigley, James P.
Reed, Steven
Roberts, Edward
Rosen, Hugh
Ruggeri, Zaverio
Russell, Paul
Saez, Enrique
Smider, Vaughn
Srinivasan, Supriya
Steinhubl, Steven
Sutcliffe, J.
Tan, Eng
Topol, Eric
Vanderklish, Peter
Vogt, Peter K.
Waalen, Jill
Wiseman, Luke
Wittenberg, Curt
Wolan, Dennis W.
Wu, Peng
Wu, Xiaohua
Yang, Xiang-Lei
Yates III, John


FL Faculty

Bohn, Laura M.
Cameron, Michael
Duckett, Derek
Gill, Matt
Griffin, Patrick
Hansen, Scott
Kamenecka, Theodore
Kissil, Joseph
Luo, Junli
McDonald, Patricia
Miller, Courtney
Niedernhofer, Laura
Phinney, Donald G.
Robbins, Paul
Scampavia, Louis
Schimmel, Paul
Smith, Roy
Spicer, Timothy


Affiliated Faculty

Cline, Hollis
Kojetin, Douglas
Lairson, Luke
Paegel, Brian
Rumbaugh, Gavin
Shen, Ben
Solt, Laura A
Su, Andrew
Wu, Chunlei


Adjunct Faculty