Role of noncanonical Wnt ligands and Ror‐family receptor tyrosine kinases in the development, regeneration, and diseases of the musculoskeletal system

Kamizaki, Koki; Endo, Mitsuharu; Minami, Yasuhiro; Kobayashi, Yasuhiro

doi:10.1002/dvdy.151

Cited by 22 publications

(26 citation statements)

References 104 publications

(192 reference statements)

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“…In vertebrates, ROR2 and ROR1 bind to non-classical Wnt5a protein through their CRD and act as receptors or co-receptors for Wnt5a to activate non-classical Wnt pathways (β-cateninindependent pathways), including planar cellular polarization pathways and Wnt-Ca 2+ pathways (Oishi et al, 2003;Yamamoto et al, 2007;Gao et al, 2011;Kamizaki et al, 2020). Recently, studies showed that the Wnt5a-ROR2 pathway was not only involved in the development of cartilage but also associated with the function of osteoblasts and osteoclasts (Chen et al, 2019;Uehara et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…As a member of ROR family receptor tyrosine kinase, receptor tyrosine kinase like orphan receptor 2 (ROR2) is a 943-amino acid transmembrane protein tyrosine kinase encoded by the ROR2 gene (van Bokhoven et al, 2000). The extracellular domains of ROR2 mainly include an immunoglobulin-like functional domain, a cysteine enrichment domain (CRD), and a kringle domain, while the intracellular domains include a tyrosine kinase domain (TKD), a proline-rich domain, two serine/threonine-rich domains, and a short C-terminal tail (Endo and Minami, 2018;Kamizaki et al, 2020). ROR2 is widely expressed in a variety of tissues, including the heart, brain, and lung and is also involved in the development of the nervous system and the skeletal system (Huang et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

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Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature

Gui

et al. 2021

Front. Cell Dev. Biol.

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PurposeROR2, a member of the ROR family, is essential for skeletal development as a receptor of Wnt5a. The present study aims to investigate the mutational spectrum of ROR2 in children with short stature and to identify the underlying molecular mechanisms.MethodsWe retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of ROR2. We subsequently examined the changes in protein expression and subcellular location in ROR2 caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a–ROR2 pathway was also examined.ResultsWe identified 12 mutations in ROR2 in 21 patients, including 10 missense, one nonsense, and one frameshift. Among all missense variants, four recurrent missense variants [c.1675G > A(p.Gly559Ser), c.2212C > T(p.Arg738Cys), c.1930G > A(p.Asp644Asn), c.2117G > A(p.Arg706Gln)] were analyzed by experiments in vitro. The c.1675G > A mutation significantly altered the expression and the cellular localization of the ROR2 protein. The c.1675G > A mutation also caused a significantly decreased expression of c-Jun. In contrast, other missense variants did not confer any disruptive effect on the biological functions of ROR2.ConclusionWe expanded the mutational spectrum of ROR2 in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in ROR2 might affect the expression of downstream Wnt5a–ROR2 pathway gene by disturbing the subcellular localization and expression of the protein.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature

Gui

et al. 2021

Front. Cell Dev. Biol.

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“…The ROR subfamily members were designated as "orphan" receptors because their ligands have not been identified for many years. Now it is known that ROR family members are receptors for Wnt family signaling molecules Wnt5a/b and Wnt16, with Wnt5a as the primary ligand (3)(4)(5)(6).…”

Section: Introductionmentioning

confidence: 99%

Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies

et al. 2021

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Receptor tyrosine kinase ROR1 plays an essential role in embryogenesis and is overexpressed in many types of malignant tumors. Studies have demonstrated that it plays an important role in oncogenesis by activating cell survival signaling events, particularly the non-canonical WNT signaling pathway. Antibody-based immunotherapies targeting ROR1 have been developed and evaluated in preclinical and clinical studies with promising outcomes. However, small molecule inhibitors targeting ROR1 are underappreciated because of the initial characterization of ROR1 as a peusdokinase. The function of ROR1 as a tyrosine kinase remains poorly understood, although accumulating evidence have demonstrated its intrinsic tyrosine kinase activity. In this review, we analyzed the structural and functional features of ROR1 and discussed therapeutic strategies targeting this kinase.

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“…The Wnt signaling pathway is widely distributed in invertebrates and vertebrates and is a highly evolutionarily conserved signaling pathway. Wnt signaling plays a crucial role in physiological processes, such as the early development of animal embryos [ 30 ], organ formation [ 31 ], and tissue regeneration [ 32 ]. Binding of the Wnt molecule to a transmembrane receptor triggers the accumulation of β -catenin in the cytoplasm and its subsequent translocation into the nucleus via interaction of the receptor with Dishevelled (DVL) and a series of cytoplasmic proteins [ 33 ].…”

Section: Introductionmentioning

confidence: 99%

miR-296-5p Inhibits the Secretion of Pulmonary Surfactants in Pulmonary Epithelial Cells via the Downregulation of Wnt7b/β-Catenin Signaling

Zhang

Chen

et al. 2021

BioMed Research International

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Neonatal respiratory distress syndrome (NRDS) is a common disease that occurs in premature infants. However, the mechanisms underlying the disease remain unclear. microRNAs (miRNAs) have been indicated to play a crucial role in the development of NRDS. In this study, we aimed to explore the regulatory mechanisms of miR-296-5p in NRDS. The expression levels of miR-296-5p in preterm infants with NRDS were determined using quantitative reverse-transcription polymerase chain reaction (RT-qPCR). A549 cells were transfected with lentiviral vectors encoding miR-296-5p, and the transfection efficiency was determined using RT-qPCR. Flow cytometry and CCK8 assay were performed to measure apoptosis and proliferation of A549 cells, respectively. The protein levels of pulmonary surfactant SP-A (SFTPA1), SP-B, Wnt7b, and β-catenin were measured using western blotting. We demonstrated an upregulation of miR-296-5p in NRDS. The miR-296-5p was successfully overexpressed in A549 cells via lentivirus transfection, and the upregulation of miR-296-5p inhibited cell proliferation and secretion of SP-A and SP-B and also induced downregulation of the Wnt7b/β-catenin in vitro. Therefore, miR-296-5p inhibits cell proliferation and secretion of pulmonary surfactants in A549 cells via downregulation of Wnt7b/β-catenin signaling.

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Role of noncanonical Wnt ligands and Ror‐family receptor tyrosine kinases in the development, regeneration, and diseases of the musculoskeletal system

Cited by 22 publications

References 104 publications

Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature

Heterozygous Recurrent Mutations Inducing Dysfunction of ROR2 Gene in Patients With Short Stature

Tyrosine Kinase ROR1 as a Target for Anti-Cancer Therapies

miR-296-5p Inhibits the Secretion of Pulmonary Surfactants in Pulmonary Epithelial Cells via the Downregulation of Wnt7b/β-Catenin Signaling

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