{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,20]],"date-time":"2026-07-20T14:18:36Z","timestamp":1784557116671,"version":"3.55.0"},"reference-count":34,"publisher":"Bioscientifica","issue":"1","license":[{"start":{"date-parts":[[2014,5,23]],"date-time":"2014-05-23T00:00:00Z","timestamp":1400803200000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/3.0\/deed.en_GB"}],"content-domain":{"domain":["jme.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2014,8]]},"abstract":"<jats:p>\n                    The interaction of receptor activator of NF\u03baB (RANK), a member of the tumour necrosis factor receptor superfamily, with RANK ligand is crucial for the formation, function and survival of osteoclasts. The role of the cytoplasmic oligomerisation domain (pre-ligand assembly domain; PLAD or \u2018IVVY\u2019 motif) in the ligand-dependent activation of downstream NF\u03baB signalling has not been studied previously. The discovery of truncating mutations of\n                    <jats:italic>TNFRSF11A<\/jats:italic>\n                    (W434X and G280X that lack the PLAD) as the cause of rare cases of osteoclast-poor osteopetrosis offered the opportunity for functional study of this region. Recapitulating the W434X mutation by transcription activator-like effector nuclease (TALEN)-mediated targeted disruption of\n                    <jats:italic>Tnfrsf11a<\/jats:italic>\n                    within the region homologous to W434X in the mouse macrophage-like cell line RAW264.7 impaired formation of osteoclast-like cells. Using overexpression studies, we demonstrated that, in contrast to WT-RANK, the absence of the PLAD in G280X-RANK and W434X-RANK prevented ligand-independent but not ligand-dependent oligomerisation. Cells expressing W434X-RANK, in which only two of the three TRAF6-binding motifs are present, continued to exhibit ligand-dependent NF\u03baB signalling. Hence, the absence of the PLAD did not prevent ligand-induced trimerisation and subsequent NF\u03baB activation of RANK, demonstrating that therapeutic targeting of the PLAD in the prevention of osteoporosis may not be as effective as proposed previously.\n                  <\/jats:p>","DOI":"10.1530\/jme-14-0077","type":"journal-article","created":{"date-parts":[[2014,5,24]],"date-time":"2014-05-24T01:53:24Z","timestamp":1400896404000},"page":"81-91","update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-1","source":"Crossref","is-referenced-by-count":5,"title":["RANK receptor oligomerisation in the regulation of NF\u03baB 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