ROR1 (inactive tyrosine-protein kinase transmembrane receptor ROR1) is a single-pass receptor of the ROR family with an extracellular cysteine-rich (Frizzled-like) and kringle domain and an intracellular pseudokinase domain. Its tyrosine-kinase domain is catalytically inactive (very low activity in vitro; it does not bind ATP), so ROR1 signals non-catalytically as a receptor/coreceptor for Wnt ligands (notably Wnt5a) in non-canonical Wnt signaling, regulating cell polarity, migration and proliferation. It is an oncofetal antigen, re-expressed in many cancers (e.g. CLL), making it a prominent immunotherapy target.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | IBA NOT GO_REF:0000033 | ACCEPT | Summary: NOT: ROR1 does not have transmembrane receptor tyrosine kinase activity. Its kinase domain is degenerate (very low activity in vitro; does not bind ATP) - an inactive/pseudokinase RTK. Reason: Correct, important negation. Retain. Supporting Evidence: file:human/ROR1/ROR1-uniprot.txt The kinase domain has very low catalytic activity in vitro |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: plasma membrane: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | IBA NOT GO_REF:0000033 | ACCEPT | Summary: NOT: ROR1 is not involved in cell-surface receptor protein tyrosine kinase signaling (as a catalytic RTK). Reason: Correct negation, consistent with the inactive kinase domain. Retain. |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: signaling receptor complex: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0030424 axon | IBA GO_REF:0000033 | ACCEPT | Summary: axon: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IBA GO_REF:0000033 | ACCEPT | Summary: positive regulation of canonical NF-kappaB signal transduction: a core biological process for ROR1. Reason: Core process consistent with ROR1's established function. |
| GO:0017147 Wnt-protein binding | IBA GO_REF:0000033 | ACCEPT | Summary: Wnt-protein binding: ROR1 binds Wnt ligands via its extracellular CRD, central to its coreceptor role. Reason: Core, ligand-binding function. Retain. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | REMOVE | Summary: Positive 'protein kinase activity' (IEA) from the protein-kinase-superfamily signature. ROR1 is an inactive/pseudokinase receptor. Reason: Electronic over-propagation contradicted by the curated NOTs and the CAUTION (degenerate kinase, no ATP binding). Remove. Supporting Evidence: file:human/ROR1/ROR1-uniprot.txt The kinase domain has very low catalytic activity in vitro |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: plasma membrane: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0015026 coreceptor activity | IEA GO_REF:0000117 | ACCEPT | Summary: Coreceptor activity: ROR1 functions as a Wnt coreceptor in non-canonical Wnt signaling. Reason: Core function consistent with the Wnt-receptor role. Retain. |
| GO:0016055 Wnt signaling pathway | IEA GO_REF:0000108 | ACCEPT | Summary: Wnt signaling pathway: a core biological process for ROR1. Reason: Core process consistent with ROR1's established function. |
| GO:0017147 Wnt-protein binding | IEA GO_REF:0000117 | ACCEPT | Summary: Wnt-protein binding: ROR1 binds Wnt ligands via its extracellular CRD, central to its coreceptor role. Reason: Core, ligand-binding function. Retain. |
| GO:0030424 axon | IEA GO_REF:0000044 | ACCEPT | Summary: axon: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0005515 protein binding | IPI PMID:22439932 NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR ... | KEEP AS NON CORE | Summary: Specific protein interaction (PMID:22439932) consistent with ROR1's scaffold/adapter role. Reason: Real interaction kept as non-core supporting evidence; the generic 'protein binding' term is itself uninformative. |
| GO:0043679 axon terminus | IEA GO_REF:0000107 | ACCEPT | Summary: axon terminus: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0048839 inner ear development | IEA GO_REF:0000107 | ACCEPT | Summary: inner ear development: a core biological process for ROR1. Reason: Core process consistent with ROR1's established function. |
| GO:0005524 ATP binding | IDA NOT PMID:24107129 A robust methodology to subclassify pseudokinases based on t... | ACCEPT | Summary: NOT: ROR1 does not bind ATP (IDA) - its degenerate kinase domain lacks nucleotide binding. Reason: Correct negation with direct evidence; underpins the pseudokinase classification. Retain. Supporting Evidence: file:human/ROR1/ROR1-uniprot.txt Does not bind ATP |
| GO:0016020 membrane | EXP PMID:27162350 ROR1 is essential for proper innervation of auditory hair ce... | ACCEPT | Summary: membrane: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0008283 cell population proliferation | IDA PMID:36949068 IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via... | KEEP AS NON CORE | Summary: cell population proliferation: a core biological process for ROR1. Reason: Cell population proliferation is a downstream physiological/oncogenic phenotype of ROR1 signaling rather than its core molecular role; kept as non-core for consistency with how the same phenotype is treated elsewhere (e.g. RHBDF1). |
| GO:0038023 signaling receptor activity | IDA PMID:36949068 IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via... | ACCEPT | Summary: Signaling receptor activity (IDA): ROR1 transduces signals as a cell-surface receptor independent of catalytic activity. Reason: Core receptor function. Retain. |
| GO:0015026 coreceptor activity | TAS PMID:24431302 Wnt signaling in midbrain dopaminergic neuron development an... | ACCEPT | Summary: Coreceptor activity: ROR1 functions as a Wnt coreceptor in non-canonical Wnt signaling. Reason: Core function consistent with the Wnt-receptor role. Retain. |
| GO:0005886 plasma membrane | IDA PMID:27162350 ROR1 is essential for proper innervation of auditory hair ce... | ACCEPT | Summary: plasma membrane: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0007605 sensory perception of sound | IMP PMID:27162350 ROR1 is essential for proper innervation of auditory hair ce... | ACCEPT | Summary: sensory perception of sound: a core biological process for ROR1. Reason: Core process consistent with ROR1's established function. |
| GO:0042813 Wnt receptor activity | IMP PMID:27162350 ROR1 is essential for proper innervation of auditory hair ce... | ACCEPT | Summary: Wnt receptor activity (IMP): ROR1 acts as a receptor/coreceptor for Wnt ligands (notably Wnt5a) - its real signaling function. Reason: Core molecular function for ROR1 as a (non-catalytic) Wnt receptor. Retain. |
| GO:0043123 positive regulation of canonical NF-kappaB signal transduction | IMP PMID:27162350 ROR1 is essential for proper innervation of auditory hair ce... | ACCEPT | Summary: positive regulation of canonical NF-kappaB signal transduction: a core biological process for ROR1. Reason: Core process consistent with ROR1's established function. |
| GO:0043679 axon terminus | ISS GO_REF:0000024 | ACCEPT | Summary: axon terminus: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0048839 inner ear development | ISS GO_REF:0000024 | ACCEPT | Summary: inner ear development: a core biological process for ROR1. Reason: Core process consistent with ROR1's established function. |
| GO:0043235 signaling receptor complex | IDA PMID:23382219 Structural basis for endosomal trafficking of diverse transm... | ACCEPT | Summary: signaling receptor complex: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0017147 Wnt-protein binding | IPI PMID:18287027 Antisera induced by infusions of autologous Ad-CD154-leukemi... | ACCEPT | Summary: Wnt-protein binding: ROR1 binds Wnt ligands via its extracellular CRD, central to its coreceptor role. Reason: Core, ligand-binding function. Retain. |
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | TAS PMID:8875995 Human neural tissues express a truncated Ror1 receptor tyros... | REMOVE | Summary: Legacy positive transmembrane RTK activity (TAS, PMID:8875995) from the original cloning report, superseded by the demonstration that the kinase domain is inactive. Reason: Outdated enzymatic claim, contradicted by the curated NOT|RTK activity and the CAUTION. Remove. Supporting Evidence: file:human/ROR1/ROR1-uniprot.txt The kinase domain has very low catalytic activity in vitro |
| GO:0005737 cytoplasm | TAS PMID:8875995 Human neural tissues express a truncated Ror1 receptor tyros... | KEEP AS NON CORE | Summary: cytoplasm: a secondary/broad localization for ROR1. Reason: Plausible but non-core (broad term or context-specific). |
| GO:0005886 plasma membrane | TAS PMID:1334494 A novel family of cell surface receptors with tyrosine kinas... | ACCEPT | Summary: plasma membrane: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0005886 plasma membrane | TAS PMID:8875995 Human neural tissues express a truncated Ror1 receptor tyros... | ACCEPT | Summary: plasma membrane: a core subcellular location for ROR1. Reason: Correct core localization. |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | TAS PMID:1334494 A novel family of cell surface receptors with tyrosine kinas... | REMOVE | Summary: Legacy positive cell-surface RTK signaling (TAS) tied to the now-refuted catalytic-receptor model. Reason: Superseded process annotation, contradicted by the curated NOT. Remove. |
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Download this section (compressed HTML)Q: Does ROR1 signaling require heterodimerization with a catalytically active partner (e.g. ROR2, RYK, or MuSK) to compensate for its dead kinase domain?
Experiment: Compare Wnt5a-dependent signaling/migration in cells expressing wild-type ROR1 vs an extracellular-CRD mutant that cannot bind Wnt.
Hypothesis: ROR1 transduces Wnt5a signals independently of any kinase activity.
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