title: Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis.
abstract: The signaling pathway downstream of stimulation of receptor activator of nuclear factor κB (RANK) by RANK ligand is crucial for osteoclastogenesis. RANK recruits TNF receptor-associated factor 6 (TRAF6) to TRAF6-binding sites (T6BSs) in the RANK cytoplasmic tail (RANKcyto) to trigger downstream osteoclastogenic signaling cascades. RANKcyto harbors an additional highly conserved domain (HCR) that also activates crucial signaling during RANK-mediated osteoclastogenesis. However, the functional cross-talk between T6BSs and the HCR in the RANK signaling complex remains unclear. To characterize the cross-talk between T6BSs and the HCR, we screened TRAF6-interacting proteins using a proteomics approach. We identified Vav3 as a novel TRAF6 binding partner and evaluated the functional importance of the TRAF6-Vav3 interaction in the RANK signaling complex. We demonstrated that the coiled-coil domain of TRAF6 interacts directly with the Dbl homology domain of Vav3 to form the RANK signaling complex independent of the TRAF6 ubiquitination pathway. TRAF6 is recruited to the RANKcyto mutant, which lacks T6BSs, via the Vav3 interaction; conversely, Vav3 is recruited to the RANKcyto mutant, which lacks the IVVY motif, via the TRAF6 interaction. Finally, we determined that the TRAF6-Vav3 interaction resulting from cross-talk between T6BSs and the IVVY motif in RANKcyto enhances downstream NF-κB, MAPK, and NFATc1 activation by further strengthening TRAF6 signaling, thereby inducing RANK-mediated osteoclastogenesis. Thus, Vav3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between T6BSs and the IVVY motif in the RANK signaling complex.
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors: Jiyeon
authors: J
authors: Yu
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors: Hyeongseok
authors: H
authors: Yun
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors: Bongjin
authors: B
authors: Shin
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors: Yongjin
authors: Y
authors: Kim
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors: Eui-Soon
authors: ES
authors: Park
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors: Seunga
authors: S
authors: Choi
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors: Jungeun
authors: J
authors: Yu
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors: Dulshara Sachini
authors: DS
authors: Amarasekara
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea.
authors: Sumi
authors: S
authors: Kim
authors: the Division of Cellular and Molecular Biology, Department of Cancer Biology, Institute of Medical Science, University of Tokyo, Tokyo 108-8639, Japan.
authors: Jun-Ichiro
authors: J
authors: Inoue
authors: the Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and.
authors: Matthew C
authors: MC
authors: Walsh
authors: the Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and.
authors: Yongwon
authors: Y
authors: Choi
authors: the Department of Biochemistry, School of Dentistry, Showa University, Shinagawaku, 142-8555, Japan.
authors: Masamichi
authors: M
authors: Takami
authors: From the Department of Microbiology and Molecular Biology, Chungnam National University, Daejeon 305-764, Korea, jrrho@cnu.ac.kr.
authors: Jaerang
authors: J
authors: Rho
mesh_terms: D020816:Amino Acid Motifs; D002460:Cell Line; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D020935:MAP Kinase Signaling System / Q000502:physiology*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav / Q000235:genetics / Q000378:metabolism*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000235:genetics / Q000378:metabolism*; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination / Q000502:physiology
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D046912:Multiprotein Complexes; D050778:NFATC Transcription Factors; C494003:NFATC1 protein, human; D051567:Proto-Oncogene Proteins c-vav; D053246:Receptor Activator of Nuclear Factor-kappa B; D048029:TNF Receptor-Associated Factor 6; C505686:TNFRSF11A protein, human; C000604754:Tifab protein, human; C496621:VAV3 protein, human
keywords: NFAT transcription factor; mitogen-activated protein kinase (MAPK); osteoclast; osteoporosis; signal transduction