Date of Award
Doctor of Philosophy (PhD)
This thesis describes the investigation of the mechanisms of signal transduction activated by tumor necrosis factor (TNF) superfamily proteins. Ligands of the TNF family engage TNF receptor (TNFR) family proteins, leading to a wide variety of cellular effects, these interactions are implicated in inflammation, immune regulation, bone homeostasis, and development. TNFR proteins lack intrinsic enzymatic activity, and are coupled to intracellular signaling cascades by TNFR associated factor (TRAF) proteins, which are cytoplasmic adaptor molecules. The roles of TRAF1, TRAF2, and TRAF6 are investigated structurally and functionally in the activation of NF-kB, AP-1, and Src-family kinases. Cbl proteins are identified as positive and negative regulators of Src-family kinase signaling. The molecular structure of TRAF6 is determined and structure-function relationships between TRAF6 and the receptors to which it binds are examined. A physiological role for TRAF1 is identified in the regulation of TRAF2. This finding elucidates the role of translocation into lipid rafts in TRAF signaling regulation. The implications of these findings are considered primarily in the reciprocal regulation of immunity and bone homeostasis by TRAF-mediated signaling pathways.
Arron, Joseph R., "Mechanisms of TRAFSignaling" (2001). Student Theses and Dissertations. 345.