Receptor activator of nuclear factor kappa B (RANK) is a tumor necrosis factor receptor (TNFR) family protein that plays an important role in the regulation of bone and immune systems. Cellular responses to RANK ligand (RANKL) and the signal transduction pathways of RANK have been well characterized in osteoclasts and osteoclast precursor cells. RANKL induces the differentiation of osteoclast precursor cells and stimulates the resorption function and survival of mature osteoclasts. The RANK signaling mechanisms involved in these responses include the recruitment of TNF receptor-associated factor proteins, the activation of transcription factors (NF-kappaB, AP-1, and NFAT2), the cascades of mitogen-activated protein kinases (ERK, JNK, and p38), and the induction of Src- and phosphatidylinositol 3-kinase-dependent Akt activation. Despite the identification of several molecular targets. a comprehensive understanding of RANK signaling requires further Studies on more complicated issues such as the temporal and spatial pattern of the engagement of signaling molecules and the precise relationship between the signaling pathway and the cellular response. (C) 2003 Elsevier Science (USA). All rights reserved.