Abstract
Rafts, cholesterol- and sphingolipid-rich membrane microdomains, have been shown to play an important role in immune cell activation. More recently rafts were implicated in the signal transduction by members of the TNF receptor (TNFR) family. In this study, we provide evidences that the raft microdomain has a crucial role in RANK (receptor activator of NF-kappaB) signaling. We found that the majority of the ectopically expressed RANK and substantial portion of endogenous TRAF2 and TRAF6 were detected in the low-density raft fractions. In addition, TRAF6 association with rafts was increased by RANKL stimulation. The disruption of rafts blocked the TRAF6 translocation by RANK ligand and impeded the interaction between RANK and TRAF6. Our observations demonstrate that proper RANK signaling requires the function of raft membrane microdomains.
Highlights
Osteoclasts are multinucleated giant cells responsible for bone resorption
When its receptor receptor activator of NF-κB (RANK) was stimulated by RANKL, several TNF receptor-associated factors (TRAFs), especially TRAF6, can be directly recruited into RANK cytoplasmic domains and may trigger downstream signaling molecules for the activation of NF-κB and mitogen activated protein kinases (MAPKs) (Darnay et al, 1998; Wong et al, 1998; Kim et al, 1999)
The essential role of RANKL, RANK, and TRAF6 were clearly demonstrated in gene-deficient mice that displayed osteopetrotic phenotype due to defective osteoclastic bone resorption (Dougall et al, 1999; Kong et al, 1999; Lomaga et al, 1999; Naito et al, 1999)
Summary
Osteoclasts are multinucleated giant cells responsible for bone resorption. These cells are differentiated from hematopoietic myeloid precursors of the monocyte/ macrophage lineage (Suda et al, 1992). Lipid rafts are specialized membrane microdomains in the plasma membranes They are enriched in glycosphingolipids and cholesterol, and incorporate specific proteins, among which are many glycosylphosphatidylinositol (GPI)-anchored proteins (Brown and London, 1998; Simons and Toomre, 2000) and Src family kinases. The association with lipid rafts of some members of the tumor necrosis factor receptor (TNFR) family, including CD40, has been reported (Vidalain et al, 2000). The association of CD40 and TRAF in raft microdomains raises the possibility that rafts may function as the signaling platform for the TNFR group of transmembrane proteins as in the case for the immune cell antigen receptors. Disruption of rafts impeded interaction between RANK and TRAF6
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