Cherubism—A familial fibrous dysplasia of the jaws

Jones, William A.; Gerrie, John; Pritchard, J. E.

doi:10.1016/0030-4220(52)90129-1

Cited by 42 publications

(23 citation statements)

References 3 publications

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“…Tankyrase-mediated 3BP2 ribosylation creates a recognition site for the E3 ubiquitin ligase RNF146, leading to its proteasomal degradation (15). Gain-of-function missense mutations in the SH3BP2 gene, which are associated with cherubism, a rare genetic syndrome characterized by bone dysplasia and remodeling of the facial bones (15)(16)(17), uncouple 3BP2 from tankyrase/RNF146, stabilize 3BP2 protein, and cause hyperactivation of SRC, SYK, and VAV. A genetically engineered mouse model of cherubism harboring one of the cherubism mutations develops hyperactive osteoclasts and a lethal systemic inflammatory disorder characterized by monocytic infiltration of visceral organs and elevated levels of TNF-α (18).…”

Section: Introductionmentioning

confidence: 99%

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

Matsumoto

LaRose

Kent

et al. 2017

Journal of Clinical Investigation

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Section: Introductionmentioning

confidence: 99%

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

Matsumoto

LaRose

Kent

et al. 2017

Journal of Clinical Investigation

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“…We have previously studied cherubism, a rare hereditary syndrome associated with severe craniofacial developmental defects in children (14,15). Cherubism arises from missense mutations in the SH3BP2 gene, which stabilize the steady-state protein levels of the adapter protein SH3-domain binding protein 2 (3BP2) (14-16).…”

Section: Introductionmentioning

confidence: 99%

Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2

Matsumoto

Rose

Kent

et al. 2016

Journal of Clinical Investigation

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Figure 2. Active ABL assembles the RUNX2-TAZ transcription factor complex required for osteoblast differentiation. (A) Primary murine osteoblasts were cultured in osteogenic medium for 14 days, and phosphotyrosine immune complexes were probed with an anti-ABL antibody. WCLs were probed with the indicated antibodies for Western blot analysis. (B) HEK293T cells were cotransfected with Flag-TAZ and RUNX2, with or without ABL (PP or KD). Flag-TAZ immune complexes were probed with an anti-RUNX2 antibody. (C) Luciferase activity from a BGLAP reporter assay in HEK293T cells cotransfected with the indicated constructs. n = 3. (D and E) HEK293T cells were cotransfected with the indicated constructs, and RUNX2 (D) or ABL (E) immune complexes were probed with an anti-ABL (D) or anti-Flag (E) antibody. (F) HEK293T cells infected with shGFP or shABL were cotransfected with RUNX2 and Flag-TAZ. The nuclear compartment was extracted from the cells, and Flag-TAZ immune complexes were probed with an anti-RUNX2 antibody. (G and H) HEK293T cells were cotransfected with WT or YF RUNX2 (G) or Flag-TAZ (H), with or without ABL (PP). RUNX2 (G) or Flag-TAZ (H) immune complexes were probed with an anti-p-Tyr antibody. (I) Primary murine osteoblasts infected with shGFP or shABL were cultured in osteogenic medium. p-Tyr or RUNX2 immune complexes were probed with an anti-RUNX2 or anti-TAZ antibody. (J) Luciferase activity from a Bglap reporter assay in primary murine osteoblasts in the presence of shGFP or shABL. n = 3. (K and L) Saos-2 cells infected with an empty vector control or an FKBP-ABL-expressing retroviral vector in the presence of shGFP (K and L), shRUNX2 (K), or shTAZ (L) were cultured in growth medium containing 50 nM FK1012. Cells were stained with alizarin red S solution. n = 3. *P < 0.05, by ANOVA with a Tukey-Kramer post-hoc test. Data represent the mean ± SEM. YAP has previously been reported to be stabilized following tyrosine phosphorylation by ABL (25). In distinction, we observed that all-tyrosine-to-phenylalanine-mutant TAZ (YF) was also stabilized by active ABL (PP) (Supplemental Figure 4F), suggesting that TAZ stabilization by ABL is not mediated by tyrosine phosphorylation. TAZ is degraded following the phosphorylation of Ser311 by LATS, which primes for the phosphorylation of Ser314 by CK1ε (26). Phosphorylated Ser314 lies in the TAZ phosphodegron and triggers binding to and subsequent ubiquitylation of TAZ by the E3-ubiquitin ligase β-TrCP (26). We hypothesized that ABL suppressed TAZ ubiquitylation through disruption of the interaction between TAZ and β-TrCP and observed that ABL (PP), but not ABL (KD), diminished the interaction between these proteins ( Figure 4F). These data demonstrate that ABL stabilizes TAZ through the suppression of its ubiquitin-mediated degradation pathway initiated by β-TrCP. The Journal of Clinical Investigation R E S E A R C H A R T I C L EABL stabilizes the TAZ-TEAD complex required for osteoblast expansion. We have shown that ABL mediated stabilization of TAZ protein and asked whet...

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“…Work from our lab and others has identified the Src family kinases (SFKs), Syk, and the Vav family of Rho guanine nucleotide exchange factors (GEFs) as 3BP2-binding partners (1), all of which are known to play important roles in osteoclast function (3)(4)(5). Cherubism is a dominantly inherited syndrome characterized by excessive maxillary and mandibular bone resorption that is associated with activated osteoclasts and inflammatory cells creating interosseous cystic lesions (6). Single missense mutations in the gene encoding the adapter protein 3BP2 result in a gain-of-function alteration in the protein and is associated with the majority of cherubism patients (7).…”

Section: Introductionmentioning

confidence: 99%

3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions

Levaot¹,

Simoncic²,

Dimitriou³

et al. 2011

J. Clin. Invest.

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A fine balance between bone resorption by osteoclasts and bone formation by osteoblasts maintains bone homeostasis. In patients with cherubism, gain-of-function mutations in 3BP2, which is encoded by SH3-domain binding protein 2 (SH3BP2), cause cystic lesions with activated osteoclasts that lead to craniofacial abnormalities. However, little is known about the function of wild-type 3BP2 in regulating bone homeostasis. Here we have shown that 3BP2 is required for the normal function of both osteoblasts and osteoclasts. Initial analysis showed that Sh3bp2 -/-mice developed osteoporosis as a result of reduced bone formation despite the fact that bone resorption was impaired. We demonstrated using reciprocal bone marrow chimeras, a cellintrinsic defect of the osteoblast and osteoclast compartments in vivo. Further, Sh3bp2 -/-osteoblasts failed to mature and form mineralized nodules in vitro, while Sh3bp2 -/-osteoclasts spread poorly and were unable to effectively degrade dentine matrix in vitro. Finally, we showed that 3BP2 was required for Abl activation in osteoblasts and Src activation in osteoclasts, and demonstrated that the in vitro defect of each cell type was restored by the respective expression of activated forms of these kinases. These findings reveal an unanticipated role for the 3BP2 adapter protein in osteoblast function and in coordinating bone homeostatic signals in both osteoclast and osteoblast lineages. Introduction3BP2 is an adapter protein that contains an N-terminal pleckstrin homology (PH) domain, a proline-rich stretch that binds to Src homology 3 (SH3) domain-containing proteins, and a C-terminal SH2 domain that binds to phosphotyrosine residues (1). 3BP2 was initially identified as a binding protein of the tyrosine kinase Abl (2). Work from our lab and others has identified the Src family kinases (SFKs), Syk, and the Vav family of Rho guanine nucleotide exchange factors (GEFs) as 3BP2-binding partners (1), all of which are known to play important roles in osteoclast function (3-5). Cherubism is a dominantly inherited syndrome characterized by excessive maxillary and mandibular bone resorption that is associated with activated osteoclasts and inflammatory cells creating interosseous cystic lesions (6). Single missense mutations in the gene encoding the adapter protein 3BP2 result in a gain-of-function alteration in the protein and is associated with the majority of cherubism patients (7). A mouse model that harbors 2 copies of a cherubism allele develops severe osteoporosis associated with highly activated osteoclasts (8).In order to elucidate the role of the wild-type form of 3BP2 in bone homeostasis, we analyzed loss-of-function mutant mice. As distinct from the osteoporotic phenotype of mice expressing the cherubism gain-of-function form of 3BP2 associated with active osteoclasts, we uncovered a complex bone phenotype in mice lacking 3BP2 characterized by loss-of-function in both the osteoclast and osteoblast lineages resulting in net decreased bone mineral density and reduced mechanical ...

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Cherubism—A familial fibrous dysplasia of the jaws

Cited by 42 publications

References 3 publications

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

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

Reciprocal stabilization of ABL and TAZ regulates osteoblastogenesis through transcription factor RUNX2

3BP2-deficient mice are osteoporotic with impaired osteoblast and osteoclast functions

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