Identification of a WNT5A-Responsive Degradation Domain in the Kinesin Superfamily Protein KIF26B

Karuna, Edith P.; Choi, Stacey S.; Scales, Michael K.; Hum, Jennie; Cohen, Michael D.; Fierro, Fernando A.; Ho, Hsin‐Yi Henry

doi:10.3390/genes9040196

Cited by 12 publications

(10 citation statements)

References 53 publications

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“…We also find suggestive evidence of association between variance in the kinesin gene KIF26B and the severity of formed HO. Based upon this finding, and prior evidence of Kif26b expression in an in vitro murine model of ectopic ossification 30 and in WNT signalling, 31,45 we demonstrate KIF26B expression in human bone and its protein in a rat model of HO; and its differential expression in human MSCs in response to an osteogenic stimulus, resulting in mineralised nodule formation. We further show that modulation of KIF26B in a murine myoblast model is sufficient to inhibit osseous trans-differentiation, an effect that is associated with ERK1/2 dysregulation.…”

Section: Discussionsupporting

confidence: 68%

Genome-wide association and functional analyses identify CASC20 and KIF26B as target loci in heterotopic ossification

Hatzikotoulas

Pickering

Clark

et al. 2019

Preprint

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Heterotopic ossification (HO) is bone formation that occurs after trauma within tissues that do not normally have the property of ossification, resulting in pain and disability.The genetic architecture of HO remains unclear. In the first genome-wide association studies of this disease, we identify the human-only long non-coding RNA-encoding gene CASC20 as a robust, replicating susceptibility locus for HO and KIF26B as a potential severity locus. We find that both CASC20 and KIF26B are expressed in human bone. Both CASC20 and KIF26B expression is upregulated upon BMP2 induced osteogenic differentiation in primary human mesenchymal stem cells, followed by RUNX2 and OSTERIX upregulation and mineralised nodule formation. A CRISPR-Cas9 mediated knockout of Kif26b inhibits BMP2-induced Runx2, Sp7/Osterix, Col1A1, Alp, and Bglap/Osteocalcin expression in a murine myocyte model of osteogenic trans-differentiation, and prevents mineralised nodule formation. These studies provide the first insights into the heritable biology of common, complex HO.

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Section: Discussionsupporting

confidence: 68%

Genome-wide association and functional analyses identify CASC20 and KIF26B as target loci in heterotopic ossification

Hatzikotoulas

Pickering

Clark

et al. 2019

Preprint

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“…DVL 1, 2, 3 are not specific to a given pathway; however, DVL2 and c-Jun N-terminal kinase (JNK) are important indicators of non-canonical WNT5A/PCP signaling activation (15,19). Recently, Susman et al described that Kinesin Family Member 26B (Kif26b) is rapidly degraded in response to non-canonical WNT signaling activation and is a highly specific marker of non-canonical signaling activation (20,21).…”

Section: Introductionmentioning

confidence: 99%

Oxidized Low-Density Lipoprotein Induces WNT5A Signaling Activation in THP-1 Derived Macrophages and a Human Aortic Vascular Smooth Muscle Cell Line

Ackers

Szymanski

Silver

et al. 2020

Front. Cardiovasc. Med.

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The pathogenesis of atherosclerosis is complex, evolves, and involves many cell types. Macrophages and vascular smooth muscle cells (VSMCs) are critically involved in atherosclerosis development and progression. Several studies have shown that WNT5A protein is abundantly expressed in human atherosclerotic lesions; however, the mechanism and role of WNT signaling pathway activation is not clearly known. Using THP-1 derived macrophages, and human aortic VSMC cells, we evaluated in vitro how oxidized low-density lipoprotein (oxLDL) and WNT5A signaling interact in these two cell lines. We used western blot, scratch assay, metabolic proliferation assay, as well as immunostaining to analyze the effect of Wnt signaling activation. The results demonstrated that oxLDL, as well as WNT5A (control), induced Disheveled-2 (DVL2) activation and Kif26b degradation, indicating activation of non-canonical Wnt signaling. We found that oxLDL and WNT5A induced FZD5-ROR2 co-localization at the cellular membrane in vitro in THP-1 derived macrophages. Box5 (FZD5 receptor antagonist) inhibited oxLDL-induced DVL2/JNK activation secondary to newly secreted WNT protein from THP-1 derived macrophages. We found that WNT3A (canonical Wnt) and WNT5A showed different roles in this VSMC cell line. These findings indicate that WNT5A is upregulated by oxLDL, promotes foam cell formation, and affects VSMC phenotype and migration in these two cell lines. Also, in these cell lines FZD5 signaling seems to be necessary for lipid accumulation and, through this mechanism, WNT5A could modulate foam cell formation. Thus, our results suggest that WNT5A may contribute to the pathogenesis of vascular disease through modulating macrophage and VSMC behavior.

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“… 5 , 50 In vitro transfection of the mutant WNT5A reporter gene explains the functional significance of the corresponding mutation that influences amino acid substitution in the epidermal growth factor-like domain (Cys-ARG). 51 …”

Section: Role Of Wnt In the Cardiovascular Systemmentioning

confidence: 99%

Roles of Wnt Signaling Pathway and ROR2 Receptor in Embryonic Development: An Update Review Article

Guo

Xing

2022

Genet Epigenet

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The Wnt family is a large class of highly conserved cysteine-rich secretory glycoproteins that play a vital role in various cellular and physiological courses through different signaling pathways during embryogenesis and tissue homeostasis 3. Wnt5a is a secreted glycoprotein that belongs to the noncanonical Wnt family and is involved in a wide range of developmental and tissue homeostasis. A growing body of evidence suggests that Wnt5a affects embryonic development, signaling through various receptors, starting with the activation of β-catenin by Wnt5a. In addition to affecting planar cell polarity and Ca2+ pathways, β-catenin also includes multiple signaling cascades that regulate various cell functions. Secondly, Wnt5a can bind to Ror receptors to mediate noncanonical Wnt signaling and a significant ligand for Ror2 in vertebrates. Consistent with the multiple functions of Wnt5A/Ror2 signaling, Wnt5A knockout mice exhibited various phenotypic defects, including an inability to extend the anterior and posterior axes of the embryo. Numerous essential roles of Wnt5a/Ror2 in development have been demonstrated. Therefore, Ror signaling pathway become a necessary target for diagnosing and treating human diseases. The Wnt5a- Ror2 signaling pathway as a critical factor has attracted extensive attention.

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Identification of a WNT5A-Responsive Degradation Domain in the Kinesin Superfamily Protein KIF26B

Cited by 12 publications

References 53 publications

Genome-wide association and functional analyses identify CASC20 and KIF26B as target loci in heterotopic ossification

Genome-wide association and functional analyses identify CASC20 and KIF26B as target loci in heterotopic ossification

Oxidized Low-Density Lipoprotein Induces WNT5A Signaling Activation in THP-1 Derived Macrophages and a Human Aortic Vascular Smooth Muscle Cell Line

Roles of Wnt Signaling Pathway and ROR2 Receptor in Embryonic Development: An Update Review Article

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