IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation

Sui, Yipeng; Liu, Zun; Park, Sehyung; Thatcher, Sean E.; Zhu, Beibei; Fernandez, Joseph; Molina, Henrik; Kern, Philip A.; Zhou, Changcheng

doi:10.1172/jci.insight.96660

Cited by 33 publications

(30 citation statements)

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“…In the present studies, using association, loss-and gain-of-function, and in vitro kinase studies, we observed ␤-catenin phosphorylation and proteasome-mediated degradation via an IKK␤-dependent mechanism. These observations are similar to the recently reported regulation of ␤-catenin via IKK␤ in mesenchymal stem cell differentiation (26), but our observations suggest that some of the effects of IKK␤ can be mediated via ␤-catenin degradation. Interestingly, deletion of the priming phosphorylation sites on Ser 33,45 or the N-terminal domain of ␤-catenin, a target of GSK3␤, did not affect ␤-catenin degradation during hyperammonemia.…”

Section: Discussionsupporting

confidence: 93%

“…In the canonical pathway, in the absence of Wnt ligand, ␤-catenin is phosphorylated at Ser 33 by glycogen synthase kinase 3␤ (GSK3␤), followed by ubiquitination and degradation in the proteasome (21)(22)(23)(24)(25). More recently, IB kinase ␤ (IKK␤) has been reported to cause the phosphorylation and degradation of ␤-catenin in mesenchymal stem cell differentiation (26), but whether this pathway is relevant in mature skeletal muscle protein synthesis is also not known.…”

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confidence: 99%

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Impaired Ribosomal Biogenesis by Noncanonical Degradation of β-Catenin during Hyperammonemia

Davuluri

Giusto

Chandel

et al. 2019

Molecular and Cellular Biology

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Increased ribosomal biogenesis occurs during tissue hypertrophy, but whether ribosomal biogenesis is impaired during atrophy is not known. We show that hyperammonemia, which occurs in diverse chronic disorders, impairs protein synthesis as a result of decreased ribosomal content and translational capacity. Transcriptome analyses, real-time PCR, and immunoblotting showed consistent reductions in the expression of the large and small ribosomal protein subunits (RPL and RPS, respectively) in hyperammonemic murine skeletal myotubes, HEK cells, and skeletal muscle from hyperammonemic rats and human cirrhotics. Decreased ribosomal content was accompanied by decreased expression of cMYC, a positive regulator of ribosomal biogenesis, as well as reduced expression and activity of β-catenin, a transcriptional activator of cMYC. However, unlike the canonical regulation of β-catenin via glycogen synthase kinase 3β (GSK3β)-dependent degradation, GSK3β expression and phosphorylation were unaltered during hyperammonemia, and depletion of GSK3β did not prevent ammonia-induced degradation of β-catenin. Overexpression of GSK3β-resistant variants, genetic depletion of IκB kinase β (IKKβ) (activated during hyperammonemia), protein interactions, and in vitro kinase assays showed that IKKβ phosphorylated β-catenin directly. Overexpressing β-catenin restored hyperammonemia-induced perturbations in signaling responses that regulate ribosomal biogenesis. Our data show that decreased protein synthesis during hyperammonemia is mediated via a novel GSK3β-independent, IKKβ-dependent impairment of the β-catenin–cMYC axis.

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Section: Discussionsupporting

confidence: 93%

mentioning

confidence: 99%

Impaired Ribosomal Biogenesis by Noncanonical Degradation of β-Catenin during Hyperammonemia

Davuluri

Giusto

Chandel

et al. 2019

Molecular and Cellular Biology

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“…Western blotting. Western blotting was also performed as previously described (62,64,65). Proteins were extracted from animal tissues or cells, quantified with the Bradford assay (Thermo Fisher Scientific; 23225), and subjected to SDS-PAGE on 8-12% gels.…”

Section: Methodsmentioning

confidence: 99%

The atypical antipsychotic quetiapine induces hyperlipidemia by activating intestinal PXR signaling

et al. 2019

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“…Furthermore, mesenchymal progenitor cells from RelB KO mice also displayed enhanced bone formation in a tibial cortical defect model . The molecular mechanism(s) by which NF‐κB inhibits OBs are poorly defined, but may include interactions with Runx2, β‐catenin, Smads, AP‐1 (Fra1), focal adhesion kinase (FAK), JNKs, and ERKs …”

Section: Introductionmentioning

confidence: 99%

“…(18) The molecular mechanism(s) by which NF-κB inhibits OBs are poorly defined, but may include interactions with Runx2, βcatenin, Smads, AP-1 (Fra1), focal adhesion kinase (FAK), JNKs, and ERKs. (14,17,18,(21)(22)(23)(24)(25)(26)(27)(28) To investigate the role of NF-κB downstream of NIK specifically in the osteolineage, we utilized Osx-Cre (29) to drive a constitutively activated form of NIK. The NIKΔTRAF3 (NT3) mice harbor a mutant allele lacking the negative-regulatory TRAF3 binding domain.…”

Section: Introductionmentioning

confidence: 99%

Conditional Activation of NF-κB Inducing Kinase (NIK) in the Osteolineage Enhances Both Basal and Loading-Induced Bone Formation

Davis

Cox

Shao

et al. 2019

Journal of Bone and Mineral Research

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Studies from global loss‐of‐function mutants suggest that alternative NF‐κB downstream of NF‐κB inducing kinase (NIK) is a cell‐intrinsic negative regulator of osteogenesis. However, the interpretation of the osteoblast and/or osteocyte contribution to the bone phenotype is complicated by simultaneous osteoclast defects in these models. Therefore, we turned to a transgenic mouse model to investigate the direct role of NIK in the osteolineage. Osx‐Cre;NT3 animals (NT3‐Cre +), which bear a constitutively active NIK allele (NT3) driven by Osx‐Cre, were compared with their Cre‐negative, Control (Ctrl) littermates. NT3‐Cre + mice had elevated serum P1NP and CTX levels. Despite this high turnover state, µCT showed that constitutive activation of NIK resulted in a net increase in basal bone mass in both cortical and cancellous compartments. Furthermore, NT3‐Cre + mice exhibited a greater anabolic response following mechanical loading compared with controls. We next performed RNA‐Seq on nonloaded and loaded tibias to elucidate possible mechanisms underlying the increased bone anabolism seen in NT3‐Cre + mice. Hierarchical clustering revealed two main transcriptional programs: one loading‐responsive and the other NT3 transgene‐driven. Gene ontology (GO) analysis indicated a distinct upregulation of receptor, kinase, and growth factor activities including Wnts, as well as a calcium‐response signature in NT3‐Cre + limbs. The promoters of these GO‐term associated genes, including many known to be bone‐anabolic, were highly enriched for multiple κB recognition elements (κB‐RE) relative to the background frequency in the genome. The loading response in NT3‐Cre + mice substantially overlapped (>90%) with Ctrl. Surprisingly, control animals had 10‐fold more DEGs in response to loading. However, most top DEGs shared between genotypes had a high incidence of multiple κB‐RE in their promoters. Therefore, both transcriptional programs (loading‐responsive and NT3 transgene‐driven) are modulated by NF‐κB. Our studies uncover a previously unrecognized role for NF‐κB in the promotion of both basal and mechanically stimulated bone formation. © 2019 American Society for Bone and Mineral Research.

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IKKβ is a β-catenin kinase that regulates mesenchymal stem cell differentiation

Cited by 33 publications

References 70 publications

Impaired Ribosomal Biogenesis by Noncanonical Degradation of β-Catenin during Hyperammonemia

Impaired Ribosomal Biogenesis by Noncanonical Degradation of β-Catenin during Hyperammonemia

The atypical antipsychotic quetiapine induces hyperlipidemia by activating intestinal PXR signaling

Conditional Activation of NF-κB Inducing Kinase (NIK) in the Osteolineage Enhances Both Basal and Loading-Induced Bone Formation

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