Dr. Zarnegar is a member of the Division of Experimental Pathology.
Dr. Zarnegar is a Tenured Professor of Pathology and a member of the Division of Experimental Pathology. His laboratory is focused on determining the physiological and pathological role of the HGF/Met axis in normal tissue homeostasis and disease processes.
Dr. Zarnegar discovered Hepatocyte Growth Factor (HGF) in the 1980's when he was a Research Assistant Professor at Duke University. Since then, he has devoted his research efforts on understanding this important signaling factor. HGF and its cell surface tyrosine kinase receptor (Met) play an important role in tissue homeostasis, and the deregulation of HGF/Met axis has pathological consequences such as cancer. An in-depth understanding of the molecular mechanisms of HGF/Met function will not only shed light on normal tissue physiology but also on understanding the bases of its pathogenic effects and thus may provide opportunities for rational drug design to combat various diseases ranging from tissue degeneration to cancer.
Through structural and functional studies, Dr. Zarnegar's laboratory has discovered novel mechanisms by which the Met receptor regulates hepatocyte growth and liver homeostasis. Specifically, his lab found that, in normal liver, the extracellular domain (a.k.a. the ectodomain) of Met directly binds to Fas (a death promoting receptor) and acts as a natural antagonist of FasL thereby prohibiting Fas aggregation and cell killing. They have determined that Fas sequestration by Met is abrogated in human fatty liver disease hence making these livers vulnerable to cell death and development of NASH. The mechanism through which liver cells die is mainly via activation of the Fas axis. Unregulated hepatocyte death occurs in a variety of hepatic diseases including hepatitis caused by chemical, viral or metabolic etiologies which may ultimately culminate in end-stage liver disease including liver cancer and hepatic failure requiring liver transplantation. Dr. Zarnegar's group has mapped the interaction region in Met and Fas to a 12 amino acid region containing a core YLGA motif in Met and show that Met and its synthetic peptide derivatives prohibit FasL binding to Fas, Fas activation and hepatocyte death in vitro and in animal models of NASH. His lab is currently expanding these structure-function studies of Met.
In a separate project, Dr. Zarnegar's lab has discovered that, in human breast cancer, the HGF gene promoter is prone to deletion mutagenesis in a DNA element located 750 bp upstream from the transcription start site. This novel HGF promoter element consists of a mononucleotide repeat of 30As and is referred to as DATE (Deoxy Adenosine Tract Element). Mutation of DATE results in reactivation/lack of proper silencing of HGF gene expression in carcinoma tissues. Normally, the HGF gene is transcriptionally silenced in differentiated breast epithelial cells. Through functional studies, they showed that DATE mutation (shortening) has profound local and global effects on the HGF promoter region by modulating chromatin structure and DNA-protein interactions leading to constitutive activation of the HGF gene promoter in human breast carcinoma cells lines. Interestingly, they found that 51% (19/37) of African Americans and 15% (8/53) of Caucasians with breast cancer harbor the truncated DATE variant (25As or less) in their breast tumors and that the truncated allele significantly associates with cancer incidence and aberrant HGF expression.
Lab Manager: Dr. Xinping Tan
Current Lab Members: Dr. Jihong Ma, Research Assistant Professor, Dr. Yong Kook Kwon, Research Associate
View Dr. Zarnegar's NIH RePORT on nih.gov
View Dr. Zarnegar's publications on PubMed
- Seneviratne, D, Ma, J, Tan, X, Kwon, YK, Muhammad, E, Melhem, M, DeFrances, MC, Zarnegar, R, Genomic Instability Causes HGF Gene Activation in Colon Cancer Cells, Promoting Their Resistance to Necroptosis. Gastroenterology 2015: 148: 181-91 PMID: 25244939
- Ma, J, Zou, C, Guo, L, Seneviratne, DS, Tan, X, Kwon, YK, An, J, Bowser, R, DeFrances, MC, Zarnegar, R, A novel Death Defying Domain in Met entraps the active site of Caspase-3 and blocks apoptosis in hepatocytes. Hepatology 2014: 5: 2010-14 PMID: 24122846
- Fafalios A, Ma J, Tan X, Stoops J, Luo J, DeFrances MC, Zarnegar R, A hepatocyte growth factor receptor (Met)-insulin receptor hybrid governs hepatic glucose metabolism. Nature Medicine 2011: 17: 1577-84. PMID: 22081023
- Ma J, DeFrances MC, Zou C, Johnson C, Ferrell R, Zarnegar R, Somatic mutation and functional polymorphism of a novel regulatory element in the HGF gene promoter causes its aberrant expression in human breast cancer. J Clin Invest 2009;119: 478-91. PMID: 19188684
- Zou C, Ma J, Wang X, Guo L, Zhu Z, Stoops J, Eaker AE, Johnson CJ, Strom S, Michalopoulos GK, DeFrances MC, Zarnegar R, Lack of Fas antagonism by Met in human fatty liver disease. Nat Med 2007;13: 1078-85. PMID: 17704785
- Wang X, DeFrances MC, Dai Y, Pediaditakis P, Johnson C, Bell A, Michalopoulos GK, Zarnegar R, A mechanism of cell survival: sequestration of Fas by the HGF receptor Met. Mol Cell 2002;9: 411-21. PMID: 11864613