ROR2 is a single-pass type I transmembrane receptor tyrosine kinase of the ROR family, with an extracellular immunoglobulin-like domain, a Frizzled-like cysteine-rich domain and a kringle domain, and an intracellular tyrosine kinase domain followed by serine/threonine- and proline-rich motifs. The cysteine-rich domain binds Wnt ligands, notably WNT5A, and ROR2 acts as a receptor or coreceptor for non-canonical Wnt/planar cell polarity signalling, where it antagonizes canonical WNT3A-driven signalling and promotes polarized cell migration. Its kinase domain retains measurable but weak activity: antibody-induced homodimerization causes autophosphorylation and ROR2 phosphorylates the scaffold YWHAB/14-3-3beta to promote osteogenesis, while other work reports very little in vitro tyrosine kinase activity, so the receptor also works through recruited kinases such as TAK1. ROR2 is expressed highly in the early embryo, is required for cartilage, growth plate and skeletal development, and is re-expressed in tumours including osteosarcoma, where it supports proliferation and migration. Loss-of-function mutations cause autosomal recessive Robinow syndrome and dominant brachydactyly type B1.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic protein kinase activity from InterPro kinase signatures. Reason: The essence is right but too general - the characterized activity is tyrosine-specific autophosphorylation and phosphorylation of YWHAB, already annotated with experimental evidence on this gene. Proposed replacements: protein tyrosine kinase activity transmembrane receptor protein tyrosine kinase activity Supporting Evidence: file:human/ROR2/ROR2-uniprot.txt Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:17717073 Homodimerization of Ror2 tyrosine kinase receptor induces 14... | ACCEPT | Summary: ROR2 phosphorylates tyrosine residues on itself and on YWHAB. Reason: Dimerization-induced autophosphorylation and in vitro phosphorylation of purified 14-3-3beta by purified ROR2 establish tyrosine kinase activity, recorded by UniProt as EC 2.7.10.1. Reports of weak in vitro activity qualify the strength but not the specificity. Supporting Evidence: PMID:17717073 Purified Ror2 phosphorylates 14-3-3beta in vitro, confirming 14-3-3beta as the first identified Ror2 substrate. file:human/ROR2/ROR2-uniprot.txt EC=2.7.10.1 |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: ROR2 phosphorylates tyrosine residues on itself and on YWHAB. Reason: Dimerization-induced autophosphorylation and in vitro phosphorylation of purified 14-3-3beta by purified ROR2 establish tyrosine kinase activity, recorded by UniProt as EC 2.7.10.1. Reports of weak in vitro activity qualify the strength but not the specificity. Supporting Evidence: PMID:17717073 Purified Ror2 phosphorylates 14-3-3beta in vitro, confirming 14-3-3beta as the first identified Ror2 substrate. file:human/ROR2/ROR2-uniprot.txt EC=2.7.10.1 |
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: ROR2 is a transmembrane receptor tyrosine kinase. Reason: The protein has an extracellular ligand-binding region, a single transmembrane segment and an intracellular kinase domain, and dimerization at the cell surface triggers autophosphorylation and downstream signalling. Supporting Evidence: PMID:17717073 We demonstrate that Ror2 homodimerizes at the cell surface, and that dimerization can be induced by a bivalent antibody. PMID:1334494 The cytoplasmic portion contains the tyrosine kinase-like domain which (in Ror2) appears to be associated with protein kinase activity in vitro |
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | IEA GO_REF:0000003 | ACCEPT | Summary: ROR2 is a transmembrane receptor tyrosine kinase. Reason: The protein has an extracellular ligand-binding region, a single transmembrane segment and an intracellular kinase domain, and dimerization at the cell surface triggers autophosphorylation and downstream signalling. Supporting Evidence: PMID:17717073 We demonstrate that Ror2 homodimerizes at the cell surface, and that dimerization can be induced by a bivalent antibody. PMID:1334494 The cytoplasmic portion contains the tyrosine kinase-like domain which (in Ror2) appears to be associated with protein kinase activity in vitro |
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | TAS PMID:1334494 A novel family of cell surface receptors with tyrosine kinas... | ACCEPT | Summary: ROR2 is a transmembrane receptor tyrosine kinase. Reason: The protein has an extracellular ligand-binding region, a single transmembrane segment and an intracellular kinase domain, and dimerization at the cell surface triggers autophosphorylation and downstream signalling. Supporting Evidence: PMID:17717073 We demonstrate that Ror2 homodimerizes at the cell surface, and that dimerization can be induced by a bivalent antibody. PMID:1334494 The cytoplasmic portion contains the tyrosine kinase-like domain which (in Ror2) appears to be associated with protein kinase activity in vitro |
| GO:0005515 protein binding | IPI PMID:22939624 Quantitative analysis of HSP90-client interactions reveals p... | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:26035863 The Meckel-Gruber syndrome protein TMEM67 controls basal bod... | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari... | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | REMOVE | Summary: Generic protein binding, mostly from one large interactome screen. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The functionally meaningful interactions of ROR2 are captured by Wnt-protein binding and MAP3K (TAK1) binding; removal does not dispute the reported interactions. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ROR2 binds ATP as a kinase cosubstrate. Reason: ROR2 catalyses transfer of the ATP gamma-phosphate to tyrosine residues, so ATP binding follows from the demonstrated catalytic activity and the conserved kinase motifs. Supporting Evidence: file:human/ROR2/ROR2-uniprot.txt Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ROR2 is a single-pass type I plasma membrane receptor. Reason: Signal sequence plus transmembrane domain define an extracellular ligand-binding region at the cell surface, and the receptor dimerizes at the cell surface; UniProt records Cell membrane, single-pass type I. Supporting Evidence: file:human/ROR2/ROR2-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I membrane protein PMID:17717073 Ror2 homodimerizes at the cell surface |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ROR2 is a single-pass type I plasma membrane receptor. Reason: Signal sequence plus transmembrane domain define an extracellular ligand-binding region at the cell surface, and the receptor dimerizes at the cell surface; UniProt records Cell membrane, single-pass type I. Supporting Evidence: file:human/ROR2/ROR2-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I membrane protein PMID:17717073 Ror2 homodimerizes at the cell surface |
| GO:0005886 plasma membrane | TAS PMID:1334494 A novel family of cell surface receptors with tyrosine kinas... | ACCEPT | Summary: ROR2 is a single-pass type I plasma membrane receptor. Reason: Signal sequence plus transmembrane domain define an extracellular ligand-binding region at the cell surface, and the receptor dimerizes at the cell surface; UniProt records Cell membrane, single-pass type I. Supporting Evidence: file:human/ROR2/ROR2-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I membrane protein PMID:17717073 Ror2 homodimerizes at the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5140741 | ACCEPT | Summary: ROR2 is a single-pass type I plasma membrane receptor. Reason: Signal sequence plus transmembrane domain define an extracellular ligand-binding region at the cell surface, and the receptor dimerizes at the cell surface; UniProt records Cell membrane, single-pass type I. Supporting Evidence: file:human/ROR2/ROR2-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I membrane protein PMID:17717073 Ror2 homodimerizes at the cell surface |
| GO:0005886 plasma membrane | TAS Reactome:R-HSA-5140747 | ACCEPT | Summary: ROR2 is a single-pass type I plasma membrane receptor. Reason: Signal sequence plus transmembrane domain define an extracellular ligand-binding region at the cell surface, and the receptor dimerizes at the cell surface; UniProt records Cell membrane, single-pass type I. Supporting Evidence: file:human/ROR2/ROR2-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000250}; Single-pass type I membrane protein PMID:17717073 Ror2 homodimerizes at the cell surface |
| GO:0007165 signal transduction | IMP PMID:19486338 Orphan receptor tyrosine kinase ROR2 as a potential therapeu... | MODIFY | Summary: Generic signal transduction. Reason: True but uninformative; ROR2 signalling is specifically receptor tyrosine kinase signalling initiated at the cell surface by Wnt ligand binding, a term already carried here. Proposed replacements: cell surface receptor protein tyrosine kinase signaling pathway |
| GO:0007165 signal transduction | TAS PMID:1334494 A novel family of cell surface receptors with tyrosine kinas... | MODIFY | Summary: Generic signal transduction. Reason: True but uninformative; ROR2 signalling is specifically receptor tyrosine kinase signalling initiated at the cell surface by Wnt ligand binding, a term already carried here. Proposed replacements: cell surface receptor protein tyrosine kinase signaling pathway |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: ROR2 initiates receptor tyrosine kinase signalling from the cell surface. Reason: Ligand- or antibody-induced dimerization of surface ROR2 triggers autophosphorylation and downstream responses such as osteogenesis and migration. Supporting Evidence: PMID:17717073 Antibody-mediated dimerization causes receptor autophosphorylation and induces functional consequences of its signaling |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: ROR2 initiates receptor tyrosine kinase signalling from the cell surface. Reason: Ligand- or antibody-induced dimerization of surface ROR2 triggers autophosphorylation and downstream responses such as osteogenesis and migration. Supporting Evidence: PMID:17717073 Antibody-mediated dimerization causes receptor autophosphorylation and induces functional consequences of its signaling |
| GO:0015026 coreceptor activity | IEA GO_REF:0000117 | ACCEPT | Summary: ROR2 acts as a Wnt coreceptor. Reason: Through its Frizzled-like cysteine-rich domain ROR2 binds WNT5A and acts with Frizzled receptors in non-canonical Wnt signalling, antagonizing canonical WNT3A signalling. Supporting Evidence: file:human/ROR2/ROR2-uniprot.txt May act as a receptor for wnt ligand WNT5A which may result in the inhibition of WNT3A-mediated signaling |
| GO:0015026 coreceptor activity | TAS PMID:24431302 Wnt signaling in midbrain dopaminergic neuron development an... | ACCEPT | Summary: ROR2 acts as a Wnt coreceptor. Reason: Through its Frizzled-like cysteine-rich domain ROR2 binds WNT5A and acts with Frizzled receptors in non-canonical Wnt signalling, antagonizing canonical WNT3A signalling. Supporting Evidence: file:human/ROR2/ROR2-uniprot.txt May act as a receptor for wnt ligand WNT5A which may result in the inhibition of WNT3A-mediated signaling |
| GO:0017147 Wnt-protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: ROR2 binds Wnt ligands. Reason: Direct interaction with WNT5B was shown in osteosarcoma cells and the family-level inference is supported by the conserved Frizzled-like cysteine-rich domain; UniProt records WNT5A as a ligand. Supporting Evidence: PMID:19486338 We also identified wingless-type MMTV integration site family, member 5B (WNT5B) as a file:human/ROR2/ROR2-uniprot.txt May act as a receptor for wnt ligand WNT5A |
| GO:0017147 Wnt-protein binding | IEA GO_REF:0000117 | ACCEPT | Summary: ROR2 binds Wnt ligands. Reason: Direct interaction with WNT5B was shown in osteosarcoma cells and the family-level inference is supported by the conserved Frizzled-like cysteine-rich domain; UniProt records WNT5A as a ligand. Supporting Evidence: PMID:19486338 We also identified wingless-type MMTV integration site family, member 5B (WNT5B) as a file:human/ROR2/ROR2-uniprot.txt May act as a receptor for wnt ligand WNT5A |
| GO:0017147 Wnt-protein binding | IPI PMID:19486338 Orphan receptor tyrosine kinase ROR2 as a potential therapeu... | ACCEPT | Summary: ROR2 binds Wnt ligands. Reason: Direct interaction with WNT5B was shown in osteosarcoma cells and the family-level inference is supported by the conserved Frizzled-like cysteine-rich domain; UniProt records WNT5A as a ligand. Supporting Evidence: PMID:19486338 We also identified wingless-type MMTV integration site family, member 5B (WNT5B) as a file:human/ROR2/ROR2-uniprot.txt May act as a receptor for wnt ligand WNT5A |
| GO:0030335 positive regulation of cell migration | IDA PMID:19486338 Orphan receptor tyrosine kinase ROR2 as a potential therapeu... | ACCEPT | Summary: ROR2 promotes cell migration. Reason: Knockdown of ROR2 in osteosarcoma cells reduces migration, and ROR2/WNT5 signalling drives polarized motility more generally. Supporting Evidence: PMID:19486338 Treatment of osteosarcoma cell lines with siRNA against ROR2 significantly inhibited cell proliferation and migration. |
| GO:0030424 axon | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Axonal localization inferred phylogenetically from ROR-family members. Reason: ROR receptors act in neurite and axon guidance in several species; for human ROR2 this is a neuronal-context compartment rather than its principal site of action, which is the plasma membrane of skeletal and mesenchymal cells. |
| GO:0030669 clathrin-coated endocytic vesicle membrane | TAS Reactome:R-HSA-5140747 | KEEP AS NON CORE | Summary: Reactome places ROR2 on clathrin-coated endocytic vesicle membranes. Reason: Receptor internalization after ligand binding is expected; a trafficking compartment secondary to the plasma membrane. |
| GO:0031435 mitogen-activated protein kinase kinase kinase binding | IPI PMID:18762249 Wnt-ligand-dependent interaction of TAK1 (TGF-beta-activated... | ACCEPT | Summary: ROR2 binds the MAP3K TAK1. Reason: TAK1 interacts with the ROR2 intracellular domain and phosphorylates its STP region, a documented and informative interaction that links ROR2 to cytosolic kinases. Supporting Evidence: PMID:18762249 TAK1 (TGF-beta activated kinase 1), a MAP3K, interacts with Ror2 and phosphorylates its intracellular carboxyterminal serine/thronine/proline-rich (STP) domain. |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: ROR2 is part of a signalling receptor complex. Reason: ROR2 homodimerizes at the cell surface and assembles with Frizzled receptors and Wnt ligands into signalling complexes. Supporting Evidence: PMID:17717073 Ror2 homodimerizes at the cell surface |
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Download this section (compressed HTML)Q: How much of ROR2 signalling requires its own catalytic activity, given reports of both autophosphorylation with a defined substrate and very weak in vitro kinase activity?
Q: Which Wnt ligands bind the ROR2 cysteine-rich domain with physiologically relevant affinity in human tissues, and how do ROR1 and ROR2 divide that ligand space?
Q: Do brachydactyly B1 (dominant, intracellular truncating) and Robinow syndrome (recessive) mutations act through different mechanisms - dominant-negative receptor complexes versus simple loss of function?
Experiment: Kinase-dead (ATP-binding site mutant) versus wild-type ROR2 knock-in in human chondrocyte or mesenchymal stem cell models, scoring WNT5A-dependent migration, YWHAB phosphorylation and osteogenic differentiation, to quantify the contribution of catalysis.
Experiment: Surface-restricted ligand binding assays (BLI or cell-surface SPR) with purified ROR2 cysteine-rich domain against the human WNT panel, to establish which Wnts are direct ligands.
Experiment: Proximity labelling from the ROR2 intracellular domain in cells stimulated with WNT5A, to define the kinase and scaffold complex (TAK1, PRTB, 14-3-3) assembled on the activated receptor.
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