Dr. Bryant G. Darnay
The University of Texas MD Anderson Cancer Center
Department of Experimental Therapeutics
- Signal Transduction
- Structure/Function of Proteins
- NF-kB Transcription Factors
- Osteoclast Development
- Ubiquitin, E3 Ubiquitin Ligases, and Deubiquitinases
My research efforts over the last 10 years primarily have focused on signaling by Receptor Activator of Nuclear factor-Kappa B (RANK) and its ligand (RANKL) that absolutely are required for the differentiation of monocytes into functional osteoclasts – the cells responsible for bone destruction. My laboratory was the first to describe the interaction of TRAFs, namely TRAF2, TRAF5 and TRAF6 with RANK and subsequently the requirement for TRAF6 in activating signaling by RANK. Following these studies, my focus became dissecting the structure and function of TRAF6 in signaling by various cytokines. The research program has evolved into understanding the non-proteasomal role of ubiquitin in signaling and developed various projects surrounding this central theme and participated in many collaborative projects based on the novel reagents and techniques we developed in the lab. More recently, we generated a conditional knockout mouse of TAK1 (a downstream target of TRAF6) in the myeloid lineage to explore the physiological role of TAK1 in osteoclastogenesis. While these mice certainly have defects in osteoclast differentiation, unexpectedly, loss of TAK1 in the myeloid lineage in mice leads to a myeloproliferative disorder with myelomonocytic characteristics that resemble human chronic myelomonocytic leukemia (CMML). These exciting and novel observations suggest that TAK1 is a critical regulator of myeloid development and its loss leads to a clinically relevant human cancer.
Our overall approach is multi-faceted and utilizes many different technologies including biochemical, molecular, cellular, structural biology, and genetically engineered knockout mouse models to understand the molecular pathways involved in signaling.
Lamothe B, Besse A, Campos AD, Webster WK, Wu H, Darnay BG. Site-specific Lys-63-linked tumor necrosis factor receptor-associated Factor 6 auto-ubiquitination is a critical determinant of IkappaB kinase activation. J Biol Chem 282(6):4102-12, 2/2007.
Besse A, Lamothe B, Campos AD, Webster WK, Maddineni U, Lin SC, Wu H, Darnay BG. TAK1-dependent signaling requires functional interaction with TAB2/TAB3. J Biol Chem 282(6):3918-28, 2/2007
Besse A, Campos AD, Webster WK, Darnay BG. TRAF-interacting protein (TRIP) is a RING-dependent ubiquitin ligase. Biochem Biophys Res Commun 359(3):660-664, 8/2007.
Lin SC, Chung JY, Lamothe B, Rajashankar K, Lu M, Lo YC, Lam AY, *Darnay BG, *Wu H, *Co-senior authors. Molecular basis for the unique deubiquitinating activity of the NF-kappaB inhibitor A20. J Mol Biol 376(2):526-40, 2/2008.
Lamothe B, Campos AD, Webster WK, Gopinathan A, Hur L, Darnay BG. The RING domain and first Zinc-finger of TRAF6 coordinate signaling by IL-1, LPS, and RANKL. J Biol Chem 283(36):24871-80, 7/2008.
Ning S, Campos AD, Darnay BG, Bentz GL, Pagano JS. TRAF6 and the three C-terminal lysine sites on IRF7 are required for its ubiquitination-mediated activation by the tumor necrosis factor receptor family member latent membrane protein 1. Mol Cell Biol 28(20):6536-46, 10/2008.
Yin Q, Lin SC, Lamothe B, Lu M, Lo YC, Hura G, Zheng L, Rich RL, Campos AD, Myszka DG, Lendard MJ, Darnay BG, Wu H. E2 interaction and dimerization in the crystal structure of TRAF6. Nat Struct Mol Biol 16(6):658-666, 5/2009. e-Pub 5/2009.
Yang W-L, Wang J, Chan C-H, Lee S-W, Campos AD, Lamothe B, Hur L, Grabiner BC, Lin X, Darnay BG, Lin H-K. The E3 Ligase TRAF6 Regulates Akt Ubiquitination and Activation. Science 325(5944):1134-8, 8/2009. e-Pub 8/2009.
Yin Q, Lamothe B, Darnay BG, Wu H. Structural basis for the lack of E2 interaction in the RING domain of TRAF2. Biochemistry 48(44):10558-67, 11/2009.