Bryant G. Darnay, Ph.D.
The primary focus of my laboratory is signal transduction by members of the TNF receptor superfamily. This family of receptors modulates many diverse physiologic responses including immune regulation, inflammation, growth proliferation and differentiation, tumoricidal activity, and apoptosis. Unlike members of the growth factor and cytokine receptor families, the TNF receptor superfamily members do not possess any known enzymatic function. Nonetheless, signals are transduced via their intracellular domains primarily through 2 novel families of adaptor proteins, i.e., death domain-containing proteins and TNF receptor-associated factors (TRAF). The TRAF family consists of 6 distinct proteins, each containing a ring and zinc finger motif in their N-termini and C-terminal domains that seem to be responsible for self-association and protein interaction. Some members of the TNF receptor family interact with TRAF molecules through a specific motif (i.e., PxQxT) within the cytoplasmic domain of the receptor. Of the known TRAF molecules, only TRAF2, TRAF5, and TRAF6 have been demonstrated to mediate signaling of NF-kappaB and JNK.

A recently described TNF receptor family member, RANK (for receptor activator of NF-kappaB), and its ligand (RANKL) promote survival of dendritic cells and differentiation of osteoclasts. RANK contains 383 amino acids (residues 234-616) in its intracellular domain, in which reside 3 putative TRAF-binding domains. My preliminary investigation indicates that TRAF2, TRAF5, and TRAF6 interact with the C-terminal 85 amino acids of RANK, although TRAF2 binds preferentially. Furthermore, overexpression of RANK stimulates JNK and NF-kappaB activation. Future directions of my research will be to eludicate signal transduction of RANK and its ligand. In collaborative efforts, we will evaluate the effectiveness of using RANKL in survival of dendritic cells during tumor antigen presentation. The results of these studies may provide an initial step in understanding the role of RANK/RANKL in dendritic cell function. Many studies have indicated the ability to pulse dendritic cells ex vivo with tumor antigens to elicit immunity to tumor or viral antigens in vivo. Thus, the knowledge gained from these studies may provide a basis for using RANKL to enhance dendritic cell function and the in vivo survival of dendritic cells as a tool for treating immunologic diseases and cancer.