Receptor activator of NF-kappaB ligand (RANKL) is the master osteoclastogenic cytokine, responsible for osteoclast (OC) differentiation, activation, and survival. Interaction of RANKL with its receptor, RANK, activates the NF-kB pathway in macrophage-lineage OC progenitors. Mice deficient in RANKL, RANK, or both the p50 and p52 subunits of NF-kB lack OCs, establishing the central role for the RANKL/RANK/NF-kB pathway of osteoclastogenesis (Ocg). NF-kB inducing kinase (NIK) is a serine/threonine non-receptor kinase in the MAP3K family thought to link a number of nokn-kinase receptors with the NF-kB pathway. NIK directly interacts with TRAFs, adaptor molecules which bind to many receptors, including RANK, and with IKB kinases (IKKs). The IKKs are substrates of, and activated by NIK. Activated IKKs phosphorylate IkBalpha, leading to its degradation and release of activated NF-kB, which translocates to the nucleus. NF-kB then stimulates transcription of genes bearing kB elements in their promoters. They discovered that NF-kB activation, in response to RANKL, is intact in NIK-deficient OC precursors. On the other hand, mice lacking NIK fail to generate OCs in vitro and are resistant to stimulated Ocg in vivo. Thus, osteoclastogenic signals exist which are distinct from NF-KB but are nonetheless dependent on NIK. They hypothesize: 1. Specific motifs within NIK regulate Ocg. 2. NIK directly binds essential osteoclastogenic components of the RANK signaling pathway.
The specific aims are to: 1. Identify motifs within NIK which regulate Ocg. 2. Identify components of the RANK signaling pathway which directly interact with NIK. To accomplish these aims, they will utilize expertise in retroviral expression and OC biology, as well as establish the new technique of yeast 2-hybrid screens.
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