RANKL coordinates multiple osteoclastogenic pathways by regulating expression of ubiquitin ligase RNF146

Matsumoto, Yoshinori; LaRose, Jose; Kent, Oliver A.; Lim, Melissa; Changoor, Adele; Zhang, Lucia; Storozhuk, Yaryna; Mao, Xiaohong; Grynpas, Marc D.; Cong, Feng; Rottapel, Robert

doi:10.1172/jci90527

Cited by 36 publications

(37 citation statements)

References 51 publications

(86 reference statements)

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“…1 H‐ 15 N HSQC‐TROSY experiments were performed on a 500 MHz Bruker Avance III NMR spectrometer using ∼400 µM N labeled RNF146(ΔN‐term) in 25 mM sodium phosphate pH 7.0, 150 mM NaCl, and 10% D 2 O. Raw NMR data was processed using NMRpipe, and analyzed in NMRviewJ (One Moon Scientific) …”

Section: Methodsmentioning

confidence: 99%

“…6,7 The tankryases (TNKSs or simply tankyrase) have particularly key roles in cell growth, division, and differentiation. [8][9][10][11][12][13][14][15][16][17] As regulators of multiple signal transduction pathways including Wnt, Src, and Hippo signaling, tankyrases have emerged as important drug targets for cancer therapies. [18][19][20] Other than sharing a PARP catalytic domain at its extreme C-terminus, the TNKS proteins have a unique domain composition when compared to other PARP enzymes [ Fig.…”

Section: Introductionmentioning

confidence: 99%

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Structural basis for tankyrase‐RNF146 interaction reveals noncanonical tankyrase‐binding motifs

DaRosa¹,

Klevit²,

Xu³

2018

Protein Science

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Poly(ADP-ribosyl)ation (PARylation) catalyzed by the tankyrase enzymes (Tankyrase-1 and -2; a.k.a. PARP-5a and -5b) is involved in mitosis, telomere length regulation, GLUT-4 vesicle transport, and cell growth and differentiation. Together with the E3 ubiquitin ligase RNF146 (a.k.a. Iduna), tankyrases regulate the cellular levels of several important proteins including Axin, 3BP2, and angiomotins, which are key regulators of Wnt, Src and Hippo signaling, respectively. These tankyrase substrates are first PARylated and then ubiquitylated by RNF146, which is allosterically activated by binding to PAR polymer. Each tankyrase substrate is recognized by a tankyrase-binding motif (TBM). Here we show that RNF146 binds directly to tankyrases via motifs in its C-terminal region. Four of these RNF146 motifs represent novel, extended TBMs, that have one or two additional amino acids between the most conserved Arg and Gly residues. The individual RNF146 motifs display weak binding, but together mediate a strong multivalent interaction with the substrate-binding region of TNKS, forming a robust one-to-one complex. A crystal structure of the first RNF146 noncanonical TBM in complex with the second ankyrin repeat domain of TNKS shows how an extended motif can be accommodated in a peptide-binding groove on tankyrases. Overall, our work demonstrates the existence of a new class of extended TBMs that exist in previously uncharacterized tankyrase-binding proteins including those of IF4A1 and NELFE.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Structural basis for tankyrase‐RNF146 interaction reveals noncanonical tankyrase‐binding motifs

DaRosa¹,

Klevit²,

Xu³

2018

Protein Science

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“…The generation of Rnf146 conditional knockout mice has been described previously (35). Rnf146 fl/fl mice were crossed with CMV-Cre (14) or Osx-Cre mice (17).…”

Section: Methodsmentioning

confidence: 99%

“…Genotyping of Rnf146 fl/fl Cre mice has been described previously (35). Floxed alleles and Cre were genotyped by PCR using the following primers: Rnf146 (forward primer, 5′-CCAGTCAGACCGATCAGGAACTGAC-3′; reverse primer, 5′-TACTGAACAGCTCTCAACTATCAACACC-3′), and Cre (forward primer, 5′-GCATTACCGGTCGATGCAACGAGTGATGAG-3′; reverse primer, 5′-GAGTGAACGAACCTGGTCGAAATCAGTGCG-3′).…”

Section: Methodsmentioning

confidence: 99%

“…We propose that RNF146 is a switch required for homeostatic bone remodeling. We have recently shown that RNF146 similarly integrates both SRC and β-catenin signaling pathways downstream of RANK ligand within the osteoclast lineage (35). RANKL-mediated suppression of RNF146 synchronizes the stabilization of 3BP2, an adapter protein required for the activation of SRC, and the stabilization of AXIN1 to shut off β-catenin activity.…”

Section: Rnf146mentioning

confidence: 99%

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Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism

Matsumoto¹,

Rose²,

Lim³

et al. 2017

Journal of Clinical Investigation

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Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

Kittaka

Yoshimoto

Schlosser

et al. 2019

Journal of Bone and Mineral Research

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Periodontitis is a bacterially induced chronic inflammatory condition of the oral cavity where tooth-supporting tissues including alveolar bone are destructed. Previously, we have shown that the adaptor protein SH3-domain binding protein 2 (SH3BP2) plays a critical role in inflammatory response and osteoclastogenesis of myeloid lineage cells through spleen tyrosine kinase (SYK). In this study, we show that SH3BP2 is a novel regulator for alveolar bone resorption in periodontitis. Micro-CT analysis of SH3BP2-deficient (Sh3bp2 −/− ) mice challenged with ligature-induced periodontitis revealed that Sh3bp2 −/− mice develop decreased alveolar bone loss (male 14.9% AE 10.2%; female 19.0% AE 6.0%) compared with wild-type control mice (male 25.3% AE 5.8%; female 30.8% AE 5.8%). Lack of SH3BP2 did not change the inflammatory cytokine expression and osteoclast induction. Conditional knockout of SH3BP2 and SYK in myeloid lineage cells with LysM-Cre mice recapitulated the reduced bone loss without affecting both inflammatory cytokine expression and osteoclast induction, suggesting that the SH3BP2-SYK axis plays a key role in regulating alveolar bone loss by mechanisms that regulate the bone-resorbing function of osteoclasts rather than differentiation. Administration of a new SYK inhibitor GS-9973 before or after periodontitis induction reduced bone resorption without affecting inflammatory reaction in gingival tissues. In vitro, GS-9973 treatment of bone marrow-derived M-CSF-dependent macrophages suppressed tartrate-resistant acid phosphatase (TRAP)-positive osteoclast formation with decreased mineral resorption capacity even when GS-9973 was added after RANKL stimulation. Thus, the data suggest that SH3BP2-SYK is a novel signaling axis for regulating alveolar bone loss in periodontitis and that SYK can be a potential therapeutic target to suppress alveolar bone resorption in periodontal diseases.

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RANKL coordinates multiple osteoclastogenic pathways by regulating expression of ubiquitin ligase RNF146

Cited by 36 publications

References 51 publications

Structural basis for tankyrase‐RNF146 interaction reveals noncanonical tankyrase‐binding motifs

Structural basis for tankyrase‐RNF146 interaction reveals noncanonical tankyrase‐binding motifs

Ubiquitin ligase RNF146 coordinates bone dynamics and energy metabolism

Alveolar Bone Protection by Targeting the SH3BP2-SYK Axis in Osteoclasts

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