Structural highlights
Disease
ROR2_HUMAN Autosomal recessive Robinow syndrome;Brachydactyly type B. The disease is caused by mutations affecting the gene represented in this entry. The disease is caused by mutations affecting the gene represented in this entry.
Function
ROR2_HUMAN Tyrosine-protein kinase receptor which may be involved in the early formation of the chondrocytes. It seems to be required for cartilage and growth plate development. Phosphorylates YWHAB, leading to induction of osteogenesis and bone formation.[1]
Publication Abstract from PubMed
The receptor tyrosine kinase ROR2 mediates noncanonical WNT5A signaling to orchestrate tissue morphogenetic processes, and dysfunction of the pathway causes Robinow syndrome, brachydactyly B, and metastatic diseases. The domain(s) and mechanisms required for ROR2 function, however, remain unclear. We solved the crystal structure of the extracellular cysteine-rich (CRD) and Kringle (Kr) domains of ROR2 and found that, unlike other CRDs, the ROR2 CRD lacks the signature hydrophobic pocket that binds lipids/lipid-modified proteins, such as WNTs, suggesting a novel mechanism of ligand reception. Functionally, we showed that the ROR2 CRD, but not other domains, is required and minimally sufficient to promote WNT5A signaling, and Robinow mutations in the CRD and the adjacent Kr impair ROR2 secretion and function. Moreover, using function-activating and -perturbing antibodies against the Frizzled (FZ) family of WNT receptors, we demonstrate the involvement of FZ in WNT5A-ROR signaling. Thus, ROR2 acts via its CRD to potentiate the function of a receptor super-complex that includes FZ to transduce WNT5A signals.
Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling.,Griffiths SC, Tan J, Wagner A, Blazer LL, Adams JJ, Srinivasan S, Moghisaei S, Sidhu SS, Siebold C, Ho HH Elife. 2024 May 23;13:e71980. doi: 10.7554/eLife.71980. PMID:38780011[2]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Liu Y, Ross JF, Bodine PV, Billiard J. Homodimerization of Ror2 tyrosine kinase receptor induces 14-3-3(beta) phosphorylation and promotes osteoblast differentiation and bone formation. Mol Endocrinol. 2007 Dec;21(12):3050-61. Epub 2007 Aug 23. PMID:17717073 doi:http://dx.doi.org/10.1210/me.2007-0323
- ↑ Griffiths SC, Tan J, Wagner A, Blazer LL, Adams JJ, Srinivasan S, Moghisaei S, Sidhu SS, Siebold C, Ho HH. Structure and function of the ROR2 cysteine-rich domain in vertebrate noncanonical WNT5A signaling. Elife. 2024 May 23;13:e71980. PMID:38780011 doi:10.7554/eLife.71980
