Edward W. Harhaj, B.A., Ph.D.
B.A. – Bucknell University
Ph.D. – Penn State College of Medicine
Associate Professor, Department of Oncology,
Johns Hopkins School of Medicine
Sidney Kimmel Comprehensive Cancer Center
1650 Orleans St., Room 351/CRB-I
Baltimore, MD 21205
Phone: (410) 502-7445 – Fax: (410) 955-0840
Key words: NF-κB, inflammation, ubiquitin, signal transduction.
We are mainly interested in the regulation of the NF-κB transcription factor, the master regulator of genes controlling innate and adaptive immunity. NF-κB is tightly regulated to ensure that activation is only transient upon virus infection or stimulation by proinflammatory cytokines. Dysregulation of NF-κB leading to its persistent activation has been linked to chronic inflammation, autoimmunity and cancer. The zinc finger protein A20 is a key negative regulator of NF-κB signaling by functioning as a ubiquitin-editing enzyme that inactivates signaling molecules such as TRAF6 and RIP1. Mice lacking A20 die prematurely of spontaneous multi-organ inflammation and cachexia. We have identified several A20 regulatory proteins that are required for the function of A20 and the termination of NF-κB signaling. In current studies, we are using gene-targeted mouse models to uncover the precise roles of these A20 regulatory proteins in restricting inflammation.
Profile: Publications and Interests
Shembade, N, N.S. Harhaj, D.J. Liebl and E.W. Harhaj. 2007. Essential role for TAX1BP1 in the termination of TNF-α, IL-1 and LPS-mediated NF-κB and JNK signaling.EMBO J. 26: 3910-22. [Highlighted in Nat.Immunol. 2007 8: 1039].
Shembade, N, N.S. Harhaj, K. Parvatiyar, N.G. Copeland, N.A. Jenkins, L.M. Matesic and E.W. Harhaj. 2008. The E3 ligase Itch negatively regulates inflammatory signaling pathways by controlling the function of the ubiquitin editing enzyme A20. Nat. Immunol. 9: 254-262. [Related News and Views published in Nat. Immunol 9: 227-9; News and Commentary published in Immunol. Cell Biol. 86: 299-300; Faculty of 1000 citation: Recommended].
Shembade, N, K. Parvatiyar, N.S. Harhaj and E.W. Harhaj. 2009. The ubiquitin-editing enzyme A20 requires RNF11 to downregulate NF-κB signaling. EMBO J. 28: 513-22.[Related Have you seen? article published in EMBO J. 28: 455-6].
Shembade, N, A. Ma and E.W. Harhaj. 2010. Inhibition of NF-κB signaling by A20 through disruption of ubiquitin enzyme complexes. Science. 327: 1135-9 [Highlighted in Nat. Immunol. 2010 11: 287; Faculty of 1000 citation: Must Read].
Shembade, N., R. Pujari, N.S. Harhaj, D.W. Abbott and E.W. Harhaj. 2011. The kinase IKKα inhibits activation of the transcription factor NF-κB by phosphorylating the regulatory molecule TAX1BP1. Nat. Immunol. 12: 834-843 [Related News and Views published in Nat. Immunol. 2011 12: 815-16].