RANK. Alternative names. Discovery. Structure. William J. Boyle* SUMMARY BACKGROUND

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1 RANK William J. Boyle* Department of Cell Biology, Amgen, Inc., One Amgen Center Drive, Thousand Oaks, CA , USA * corresponding author tel: , fax: , bboyle@amgen.com DOI: /rwcy SUMMARY RANK is a novel member of the TNFR superfamily that is capable of activating the NFB and JNK pathways during cell survival. It was originally cloned from a dendritic cell cdna library suggesting a role in modulating dendritic cell function(s) during regulation of immune responses. RANK is one of the largest TNFR-related proteins, characterized as having four cysteine-rich repeats motifs in its extracellular domain, and a long intracellular signaling domain. The intracellular domain is now known to bind to members of the TRAF family of signal transducers, which mediate the activation of NFB and JNK following ligand binding. RANK is expressed at very high levels on osteoclast precursors, and is the hematopoietic cell surface protein that mediates the osteoclastogenic effects of RANKL. Since RANKL induction by calciotropic hormones and pro-resorptive cytokines is known to regulate bone density and calcium metabolism, RANK is implicated as the osteoclast receptor that integrates these humoral signals during physiologic conditions and during disease. BACKGROUND Discovery The TNFR-related protein RANK (receptor activator of NFB) was first identified as an interesting EST sequence obtained from a dendritic cell cdna library (Anderson et al., 1997). It is now known to be an important component of the OPG±RANKL± RANK axis involved in regulating bone and immune homeostasis. The full-length cdna encoded a novel TNFR-related protein, and was predicted to be involved in regulating dendritic cell function(s) during adaptive immune responses. Functional analysis of the receptor in mammalian cell lines indicated that, like other TNFR family members, RANK was capable of activating the transcription factor NFB. A ligand for RANK (RANKL) was expression cloned from a T cell line library using a soluble receptor fusion dimer. RANK was also identified by two independent groups as the receptor that regulated osteoclastogenesis mediated by osteoclast differentiation factor (ODF) or osteoprotegerin ligand (OPGL) (Nakagawa et al., 1998; Hsu et al., 1999). Interestingly, RANKL/ODF/OPGL/TRANCE was also identified as a T cell protein whose expression was controlled by calcineurin-regulated transcription factors during activation (Wong et al., 1997). Thus, the various experimental approaches used to identify both RANK and RANKL strongly implicated a role for this receptor in regulating T cell and dendritic cell interactions. In addition, cell biological and molecular genetic analysis in mouse has revealed an essential function in regulating osteoclast differentiation and activation during bone remodeling and metabolism (see Suda et al., 1999, for review). Alternative names ODFR, osteoclast differentiation factor receptor (Nakagawa et al., 1999). ODAR, osteoclast differentiation and activation receptor (Hsu et al., 1999). TRANCE-R, TRANCE receptor (Wong et al., 1998). Structure The human RANK polypeptide is a 616 amino acid type I transmembrane protein that is functionally

2 1692 William J. Boyle divided into two regions (Anderson et al., 1997). The N-terminal region of the protein is the extracellular ligand-binding domain of the protein that is displayed on the cell surface. The C-terminal region of the receptor is the cytoplasmic, signal-transducing portion that effects cellular metabolic functions in response to activation by ligand. Main activities and pathophysiological roles Activation of RANK by overexpression in transfected cells, or by treatment of receptor-bearing cells in vitro with soluble RANKL (a.k.a. TRANCE/ ODF/OPGL), has been shown to stimulate signal transduction leading to the activation of NFB (Anderson et al., 1997; Darney et al., 1999, Hsu et al., 1999). The mechanism for this is described below, but is known to involve cytoplasmic factors that belong to the TRAF family of proteins. RANK activation has also been shown to rapidly stimulate Jun N-terminal kinase (JNK/SPK), leading to activation of AP-1 related transcription factors (Wong et al., 1997; Galibert et al., 1998; Hsu et al., 1999). Our current view of RANK is that it is involved in both immune and bone homeostasis. RANK was identified as a dendritic surface receptor, indicating a potential role in modulating dendritic cell differentiation and survival. Soluble RANKL can act as a costimulatory factor during antigen presentation during in vitro culture (Anderson et al., 1997), and impacts the survival of dendritic cells during in vitro culture (Wong et al., 1997). The effects mediated by RANKL on dendritic cell function are dependent on native folding of this cytokine, and can be blocked by the addition of a soluble RANK-Ig fusion protein. RANK has also been identified as the intrinsic hematopoietic cell surface determinant required for the differentiation and activation of the osteoclast (Nakagawa et al., 1998; Hsu et al., 1999). RANK is expressed at very high levels on osteoclast progenitor cells (Lacey et al., 1998; Hsu et al., 1999). Addition of soluble RANKL to bone marrow cultures in the presence of CSF-1 (M-CSF) stimulates osteoclastogenesis and the activation of mature osteoclasts to resorb bone via binding to RANK (Hsu et al., 1999; Burgess et al., 1999). These effects can be blocked by the addition of either OPG or soluble RANK-Ig. Recombinant soluble RANK-Ig can block osteoclastogenesis and activation when administered to mice, leading to increases in bone mass (Hsu et al., 1999). GENE Accession numbers Human and mouse cdna sequences: AF AF AF AF Sequence See Figure 1. PROTEIN Accession numbers Human RANK protein: AF Sequence See Figure 2. Description of protein Human RANK is a TNFR-related, type I transmembrane protein of 616 amino acid residues (Figure 3), whereas the mouse polypeptide is 625 residues. A hydrophobic signal peptide of 29 amino acids located at the extreme N-terminus, and is removed during synthesis. The C-terminal extracellular domain is composed of four tandem cysteine-rich pseudo repeat sequences (I±IV) that are characteristic of this family (Smith et al., 1994), followed by a stalk of about 17 residues. The pseudo repeat sequences are involved in ligand binding, and are most closely related to domains I±IV of CD40, a TNFR-related protein important for B cell maturation and activation. A hydrophobic sequence of about 23 amino acids forms a membrane-spanning domain and helps to define the extracellular domain of this receptor. The C-terminal 383 amino acid residues forms the cytoplasmic region or RANK, and is one of the longest cytoplasmic domains of receptors in this class. This region of the protein has been shown to bind to a class of cytoplasmic tumor necrosis factor receptorassociated factors (TRAFs), which are involved in ligand-induced signal transduction leading to the activation of NFB and JNK/SAPK pathways (Arch et al., 1998).

3 RANK 1693 Figure 1 Nucleotide sequence for human RANK. Figure 2 Amino acid sequence for human RANK protein. The hydrophobic signal peptide and transmembrane domain are underlined. Relevant homologies and species differences The mouse and human RANK cdnas have been cloned and sequenced, and their protein products compared (Anderson et al., 1997). The human and mouse proteins are about 85% identical, with sequence gaps due to the fact that the murine protein is longer. All of the cysteine residues located in the fulllength mature proteins (residues 29±194) are conserved

4 1694 William J. Boyle Figure 3 The primary structure of the RANK polypeptide. The extracellular domain contains a short hydrophobic signal peptide (black box), four tandem cysteine-rich pseudo repeat sequences (I±IV), and a short stock region. A hydrophobic transmembrane domain anchors the RANK protein to the cell membrane. The cytoplasmic region contains at least three functional TRAFbinding sites indicated by the hatched bars. The amino acid coordinates for the various RANK structural features are listed below. and in identical positions. RANK is most closely related to the TNFR-related protein CD40, and is about 40% similar in the ligand-binding domain. Affinity for ligand(s) Various lines of evidence suggest that RANKL is the major, if not sole, ligand for RANK. Mice in which either the RANK (Dougall et al., 1999; Li et al., 2000) or RANKL (OPGL) (Kong et al., 1999a) genes have been disrupted by homologous recombination have near identical phenotypes with respect to bone metabolism and lymph node organogenesis. Biochemical analysis of surface proteins found on primary marrow-derived osteoclast progenitors indicates that RANK is the only protein present on these cells that interacts with soluble RANKL (Hsu et al., 1999; Nakagawa et al., 1998). Soluble RANK-Ig fusion protein (srank-ig) and RANKL binding coefficients have been determined by BIAcore and solution binding, and found to be in the range of M (Hsu et al., 1999). Osteoprotegerin, a secreted RANKL neutralizing receptor, binds to RANKL with approximately 10±100 times higher affinity ( ) using these same assays. In support of this difference in affinity for the same ligand, OPG and srank-ig have similar differences in EC 50 values for neutralizing RANKL-induced osteoclastogenesis in vitro and in vivo (Hsu et al., 1999). Cell types and tissues expressing the receptor See Table 1. Regulation of receptor expression Little is actually known about the regulation of RANK expression in cells and tissues. Like many Table 1 Organs and tissues Cell types Cell lines Cell types and tissues expressing the receptor Cartilaginous bone primordia during fetal development Intestinal epithelium Kidney Liver Bone and growth plate cartilage Lymph node Spleen Thymus Heart Hypertrophic chondrocytes Osteoclast progenitors Myeloid precursors B cells, activated Intestinal epithelium (small and large) Dendritic cells Foreskin fibroblasts RAW (murine macrophage) KG-1 (human myeloid leukemia) K562 (human erythroleukemia) LIM 1863 (human colorectal carcinoma) MP-1 (human lymphoblastoid) A-172 (human glioblastoma) W1-26 (human lung fibroblast, SV-40 transformed) receptors, regulation of its activity is via ligand binding, and not necessarily at the transcriptional level. Cell types bearing this receptor are likely to acquire expression during development and lineage allocation, such as in the osteoclast. RANK expression is detected early during hematopoietic development

5 RANK 1695 from stem cells, and is found on early myeloblast cell lines such as KG-1 and K562 (Anderson et al., 1997; Lacey et al., 1998). RANK expression on the surface of hematopoietic precursor cells is the key determinant that typifies the osteoclast progenitor (Lacey et al., 1998; Hsu et al., 1999; Li et al., 2000). Anderson et al. (1997) have identified cells that express high levels of RANK mrna, but do not express surface protein that crossreacts with anti-rank antibodies, suggesting that posttranscriptional mechanisms regulate surface localization of the receptor. Interestingly, activation by the cytokines IL-4 and TGF1 induce surface expression in these cells. Osteoclast progenitors express very high levels of RANK mrna and surface receptor (Lacey et al., 1998; Hsu et al., 1999). During differentiation into mature osteoclasts, RANK expression is downregulated, although the receptor is still present and able to bind and respond to soluble RANKL (Burgess et al., 1999). The mouse RANK transcript is expressed in the cartilaginous primordia of bone during embryonic development, then later is expressed in the intestine, kidney, lung, and bone (Hsu et al., 1999). In situ hybridization of embryonic and adult mouse bone indicates that RANK is expressed at sites of robust bone resorption and remodeling, such as in the growth plate cartilage region. In addition, RANK is expressed on hypertrophic chondrocytes, suggesting a role in regulating growth plate physiology. In support of this concept, mice deficient in RANKL have developmental alterations in chondrocyte development, and have abnormal-looking growth plate cartilage (Kong et al., 1999a). Release of soluble receptors The mature RANK polypeptide has not been shown to be cleaved from the cell surface, releasing a soluble ectodomain. However, as mentioned above, posttranscriptional regulation of RANK is thought to occur, and this could involve cleavage of the extracellular domain. If this occurs, this could provide a mechanism for modulating the effects of RANKL during immune and bone homeostasis. Osteoprotegerin is a known secreted inhibitor of RANKL. SIGNAL TRANSDUCTION The primary structure of RANK suggests that it mediates the effects of RANKL in a fashion similar to that of other TNRF-related proteins when they engage their cognate ligands: induction of cellular metabolic processes via the activation of signal transducing cytoplasmic factors. RANK contains no death domain motifs, and is not believed to play a role in mediating apoptosis. In contrast, its structure is more related to receptors such as CD40, which tend to promote cell survival and can stimulate differentiation. RANK was first characterized as a dendritic cell surface protein proposed to function in T cell and dendritic cell interactions during the immune response. Wong et al. (1997) first reported that RANKL (TRANCE) could stimulate JNK/ SAPK activity in treated cells, suggesting that RANK was involved in stimulating cell activation mechanisms. RANK itself was first characterized as a receptor-like protein capable of stimulating the transcription factor NFB (Anderson et al., 1997). These data suggested that two major cellular signaling pathways, JNK/SAPK and NFB, were regulated by activation of this receptor. Activation of RANK on osteoclast progenitor cells leads to the rapid stimulation of JNK activity, and subsequently the induction of osteoclast-specific gene expression (Lacey et al., 1998; Hsu et al., 1999). Apparently, NFB is not activated during this process, but is already constitutively active at this stage of osteoclast precursor development. However, RANK present on mature osteoclasts responds to ligand treatment by induction of both JNK/SAPK and NFB activity, and these functions both appear to be critical for osteoclast survival and activation (Jimi et al., 1999). The RANK cytoplasmic domain is about 383 amino acids in, and contains no obvious structural features that imply a signaling mechanism. Other members of the TNFR family are known to mediate signal transduction via cytoplasmic factors belong to the TRAF family of proteins (Arch et al., 1998). RANK presumably mediates the activation of the transcription factor NFB and JNK/SAPK activity by coupling with this class of cytoplasmic factors. The TRAF family members 1, 2, 3, 5, and 6 were all found to interact with the cytoplasmic domain of RANK in vitro (Galibert et al., 1998; Wong et al., 1998; Darney et al., 1999; Hsu et al., 1999) (Figure 4). Putative TRAF-binding sites have been found at several locations within the RANK cytoplasmic domain of about 5±6 amino acids in length (Darney et al., 1999). In cultured cells, TRAF2, 5, and 6 interactions with the RANK cytoplasmic domain have been detected (Galibert et al., 1998; Darney et al., 1999; Hsu et al., 1999). Both TRAF2 and TRAF5 have been shown to bind within the same sites at the very C-terminus of the protein, while TRAF6 binds to a two potential juxtaposed sites lying between amino acid residues 340 to 358 (Galibert et al., 1998; Hsu et al., 1999). Yeast two-hybrid interaction screening

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