ROR1

# yaml-language-server: $schema=../../../src/ai_gene_review/schema/gene_review.yaml
id: Q01973
gene_symbol: ROR1
product_type: PROTEIN
status: DRAFT
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: 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.
alternative_products:
- name: Long
  id: Q01973-1
- name: Short (T-ROR1)
  id: Q01973-2
  sequence_note: VSP_005008
- name: '3'
  id: Q01973-3
  sequence_note: VSP_043663, VSP_043664
existing_annotations:
- term:
    id: GO:0004714
    label: transmembrane receptor protein tyrosine kinase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  negated: true
  review:
    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.'
    action: ACCEPT
    reason: Correct, important negation. Retain.
    supported_by:
    - reference_id: file:human/ROR1/ROR1-uniprot.txt
      supporting_text: The kinase domain has very low catalytic activity in vitro
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'plasma membrane: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0007169
    label: cell surface receptor protein tyrosine kinase signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  negated: true
  review:
    summary: 'NOT: ROR1 is not involved in cell-surface receptor protein tyrosine kinase signaling (as
      a catalytic RTK).'
    action: ACCEPT
    reason: Correct negation, consistent with the inactive kinase domain. Retain.
- term:
    id: GO:0043235
    label: signaling receptor complex
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: part_of
  review:
    summary: 'signaling receptor complex: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: is_active_in
  review:
    summary: 'axon: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: 'positive regulation of canonical NF-kappaB signal transduction: a core biological process
      for ROR1.'
    action: ACCEPT
    reason: Core process consistent with ROR1's established function.
- term:
    id: GO:0017147
    label: Wnt-protein binding
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: 'Wnt-protein binding: ROR1 binds Wnt ligands via its extracellular CRD, central to its coreceptor
      role.'
    action: ACCEPT
    reason: Core, ligand-binding function. Retain.
- term:
    id: GO:0004672
    label: protein kinase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  qualifier: enables
  review:
    summary: Positive 'protein kinase activity' (IEA) from the protein-kinase-superfamily signature. ROR1
      is an inactive/pseudokinase receptor.
    action: REMOVE
    reason: Electronic over-propagation contradicted by the curated NOTs and the CAUTION (degenerate kinase,
      no ATP binding). Remove.
    supported_by:
    - reference_id: file:human/ROR1/ROR1-uniprot.txt
      supporting_text: The kinase domain has very low catalytic activity in vitro
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'plasma membrane: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0015026
    label: coreceptor activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: 'Coreceptor activity: ROR1 functions as a Wnt coreceptor in non-canonical Wnt signaling.'
    action: ACCEPT
    reason: Core function consistent with the Wnt-receptor role. Retain.
- term:
    id: GO:0016055
    label: Wnt signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000108
  qualifier: involved_in
  review:
    summary: 'Wnt signaling pathway: a core biological process for ROR1.'
    action: ACCEPT
    reason: Core process consistent with ROR1's established function.
- term:
    id: GO:0017147
    label: Wnt-protein binding
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: enables
  review:
    summary: 'Wnt-protein binding: ROR1 binds Wnt ligands via its extracellular CRD, central to its coreceptor
      role.'
    action: ACCEPT
    reason: Core, ligand-binding function. Retain.
- term:
    id: GO:0030424
    label: axon
  evidence_type: IEA
  original_reference_id: GO_REF:0000044
  qualifier: located_in
  review:
    summary: 'axon: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:22439932
  qualifier: enables
  review:
    summary: Specific protein interaction (PMID:22439932) consistent with ROR1's scaffold/adapter role.
    action: KEEP_AS_NON_CORE
    reason: Real interaction kept as non-core supporting evidence; the generic 'protein binding' term
      is itself uninformative.
- term:
    id: GO:0043679
    label: axon terminus
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: located_in
  review:
    summary: 'axon terminus: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0048839
    label: inner ear development
  evidence_type: IEA
  original_reference_id: GO_REF:0000107
  qualifier: involved_in
  review:
    summary: 'inner ear development: a core biological process for ROR1.'
    action: ACCEPT
    reason: Core process consistent with ROR1's established function.
- term:
    id: GO:0005524
    label: ATP binding
  evidence_type: IDA
  original_reference_id: PMID:24107129
  qualifier: enables
  negated: true
  review:
    summary: 'NOT: ROR1 does not bind ATP (IDA) - its degenerate kinase domain lacks nucleotide binding.'
    action: ACCEPT
    reason: Correct negation with direct evidence; underpins the pseudokinase classification. Retain.
    supported_by:
    - reference_id: file:human/ROR1/ROR1-uniprot.txt
      supporting_text: Does not bind ATP
- term:
    id: GO:0016020
    label: membrane
  evidence_type: EXP
  original_reference_id: PMID:27162350
  qualifier: located_in
  review:
    summary: 'membrane: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0008283
    label: cell population proliferation
  evidence_type: IDA
  original_reference_id: PMID:36949068
  qualifier: involved_in
  review:
    summary: 'cell population proliferation: a core biological process for ROR1.'
    action: KEEP_AS_NON_CORE
    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).
- term:
    id: GO:0038023
    label: signaling receptor activity
  evidence_type: IDA
  original_reference_id: PMID:36949068
  qualifier: enables
  review:
    summary: 'Signaling receptor activity (IDA): ROR1 transduces signals as a cell-surface receptor independent
      of catalytic activity.'
    action: ACCEPT
    reason: Core receptor function. Retain.
- term:
    id: GO:0015026
    label: coreceptor activity
  evidence_type: TAS
  original_reference_id: PMID:24431302
  qualifier: enables
  review:
    summary: 'Coreceptor activity: ROR1 functions as a Wnt coreceptor in non-canonical Wnt signaling.'
    action: ACCEPT
    reason: Core function consistent with the Wnt-receptor role. Retain.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:27162350
  qualifier: located_in
  review:
    summary: 'plasma membrane: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0007605
    label: sensory perception of sound
  evidence_type: IMP
  original_reference_id: PMID:27162350
  qualifier: involved_in
  review:
    summary: 'sensory perception of sound: a core biological process for ROR1.'
    action: ACCEPT
    reason: Core process consistent with ROR1's established function.
- term:
    id: GO:0042813
    label: Wnt receptor activity
  evidence_type: IMP
  original_reference_id: PMID:27162350
  qualifier: enables
  review:
    summary: 'Wnt receptor activity (IMP): ROR1 acts as a receptor/coreceptor for Wnt ligands (notably
      Wnt5a) - its real signaling function.'
    action: ACCEPT
    reason: Core molecular function for ROR1 as a (non-catalytic) Wnt receptor. Retain.
- term:
    id: GO:0043123
    label: positive regulation of canonical NF-kappaB signal transduction
  evidence_type: IMP
  original_reference_id: PMID:27162350
  qualifier: involved_in
  review:
    summary: 'positive regulation of canonical NF-kappaB signal transduction: a core biological process
      for ROR1.'
    action: ACCEPT
    reason: Core process consistent with ROR1's established function.
- term:
    id: GO:0043679
    label: axon terminus
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: located_in
  review:
    summary: 'axon terminus: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0048839
    label: inner ear development
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  qualifier: involved_in
  review:
    summary: 'inner ear development: a core biological process for ROR1.'
    action: ACCEPT
    reason: Core process consistent with ROR1's established function.
- term:
    id: GO:0043235
    label: signaling receptor complex
  evidence_type: IDA
  original_reference_id: PMID:23382219
  qualifier: part_of
  review:
    summary: 'signaling receptor complex: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0017147
    label: Wnt-protein binding
  evidence_type: IPI
  original_reference_id: PMID:18287027
  qualifier: enables
  review:
    summary: 'Wnt-protein binding: ROR1 binds Wnt ligands via its extracellular CRD, central to its coreceptor
      role.'
    action: ACCEPT
    reason: Core, ligand-binding function. Retain.
- term:
    id: GO:0004714
    label: transmembrane receptor protein tyrosine kinase activity
  evidence_type: TAS
  original_reference_id: PMID:8875995
  qualifier: enables
  review:
    summary: Legacy positive transmembrane RTK activity (TAS, PMID:8875995) from the original cloning
      report, superseded by the demonstration that the kinase domain is inactive.
    action: REMOVE
    reason: Outdated enzymatic claim, contradicted by the curated NOT|RTK activity and the CAUTION. Remove.
    supported_by:
    - reference_id: file:human/ROR1/ROR1-uniprot.txt
      supporting_text: The kinase domain has very low catalytic activity in vitro
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:8875995
  qualifier: located_in
  review:
    summary: 'cytoplasm: a secondary/broad localization for ROR1.'
    action: KEEP_AS_NON_CORE
    reason: Plausible but non-core (broad term or context-specific).
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:1334494
  qualifier: located_in
  review:
    summary: 'plasma membrane: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0005886
    label: plasma membrane
  evidence_type: TAS
  original_reference_id: PMID:8875995
  qualifier: located_in
  review:
    summary: 'plasma membrane: a core subcellular location for ROR1.'
    action: ACCEPT
    reason: Correct core localization.
- term:
    id: GO:0007169
    label: cell surface receptor protein tyrosine kinase signaling pathway
  evidence_type: TAS
  original_reference_id: PMID:1334494
  qualifier: involved_in
  review:
    summary: Legacy positive cell-surface RTK signaling (TAS) tied to the now-refuted catalytic-receptor
      model.
    action: REMOVE
    reason: Superseded process annotation, contradicted by the curated NOT. Remove.
references:
- id: GO_REF:0000002
  title: GO annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified annotations to orthologs by curator judgment
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000044
  title: GO annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary mapping
  findings: []
- id: GO_REF:0000052
  title: GO annotation based on curation of immunofluorescence data (HPA)
  findings: []
- id: GO_REF:0000107
  title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using Ensembl
    Compara
  findings: []
- id: GO_REF:0000108
  title: Automatic assignment of GO terms using logical inference, based on inter-ontology links
  findings: []
- id: GO_REF:0000117
  title: Automatic GO annotation from UniProtKB-KW mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/ROR1/ROR1-uniprot.txt
  title: UniProt entry for ROR1
  findings: []
- id: PMID:1334494
  title: A novel family of cell surface receptors with tyrosine kinase-like domain.
  findings:
  - statement: Early characterization placing ROR1 as a cell-surface receptor tyrosine kinase (legacy
      classification).
    supporting_text: receptor tyrosine kinase
  reference_review:
    relevance: LOW
    correctness: UNVERIFIED
    review_notes: Legacy RTK reference; basis of a TAS PTK-signaling annotation now REMOVEd.
- id: PMID:18287027
  title: Antisera induced by infusions of autologous Ad-CD154-leukemia B cells identify ROR1 as an oncofetal
    antigen and receptor for Wnt5a.
  findings:
  - statement: ROR1 is an oncofetal antigen and a receptor for Wnt5a, supporting its Wnt-protein binding
      / Wnt receptor function.
    supporting_text: identify ROR1 as an oncofetal antigen and receptor for Wnt5a
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Primary evidence for ROR1 as a Wnt5a receptor.
- id: PMID:22439932
  title: NKX2-1/TITF1/TTF-1-Induced ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma.
  findings:
  - statement: ROR1 sustains EGFR survival signaling in lung adenocarcinoma (a protein-interaction / signaling
      context).
    supporting_text: ROR1 is required to sustain EGFR survival signaling in lung adenocarcinoma
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Disease/interaction context; supports protein binding only.
- id: PMID:23382219
  title: Structural basis for endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins.
  findings:
  - statement: ROR1 is an endosomal-trafficking cargo of PX-FERM proteins (membrane/localization context).
    supporting_text: endosomal trafficking of diverse transmembrane cargos by PX-FERM proteins
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Trafficking/localization context (signaling receptor complex).
- id: PMID:24107129
  title: A robust methodology to subclassify pseudokinases based on their nucleotide-binding properties.
  findings:
  - statement: ROR1 is classified as a pseudokinase that does not bind nucleotide, supporting the NOT
      ATP binding annotation.
    supporting_text: A robust methodology to subclassify pseudokinases based on their nucleotide-binding
      properties
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Supports the pseudokinase classification and the curated NOT|ATP binding.
- id: PMID:24431302
  title: Wnt signaling in midbrain dopaminergic neuron development and regenerative medicine for Parkinson's
    disease.
  findings:
  - statement: Review of Wnt signaling in dopaminergic neuron development; cited for ROR1 coreceptor activity.
    supporting_text: Wnt signaling in midbrain dopaminergic neuron development
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: Review supporting the coreceptor-activity TAS annotation.
- id: PMID:27162350
  title: ROR1 is essential for proper innervation of auditory hair cells and hearing in humans and mice.
  findings:
  - statement: ROR1 is essential for innervation of auditory hair cells and hearing, and acts as a Wnt
      receptor (supports Wnt receptor activity and sensory perception of sound).
    supporting_text: ROR1 is essential for proper innervation of auditory hair cells and hearing
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: Source of the IMP Wnt receptor activity and inner-ear/hearing annotations.
- id: PMID:36949068
  title: IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis.
  findings:
  - statement: IGFBP5 is a ROR1 ligand; ROR1 functions as a signaling receptor promoting invasion via
      a ROR1/HER2-CREB axis (supports signaling receptor activity).
    supporting_text: IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling
      axis
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Supports signaling-receptor activity and a proliferation/invasion phenotype.
- id: PMID:8875995
  title: Human neural tissues express a truncated Ror1 receptor tyrosine kinase, lacking both extracellular
    and transmembrane domains.
  findings:
  - statement: Original report describing Ror1 as a receptor tyrosine kinase family member (the legacy
      RTK classification later superseded by the pseudokinase finding).
    supporting_text: a member of the receptor tyrosine kinase
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: Basis of the legacy TAS 'transmembrane RTK activity' annotation now REMOVEd as superseded.
aliases:
- NTRKR1
- Inactive tyrosine-protein kinase transmembrane receptor ROR1
- Neurotrophic tyrosine kinase receptor-related 1
core_functions:
- description: Catalytically inactive (pseudokinase) receptor tyrosine kinase that functions as a Wnt
    (Wnt5a) receptor/coreceptor in non-canonical Wnt signaling, transducing signals non-catalytically.
  molecular_function:
    id: GO:0042813
    label: Wnt receptor activity
  directly_involved_in:
  - id: GO:0016055
    label: Wnt signaling pathway
  locations:
  - id: GO:0005886
    label: plasma membrane
  supported_by:
  - reference_id: file:human/ROR1/ROR1-uniprot.txt
    supporting_text: The kinase domain has very low catalytic activity in vitro
suggested_questions:
- question: Does ROR1 signaling require heterodimerization with a catalytically active partner (e.g. ROR2,
    RYK, or MuSK) to compensate for its dead kinase domain?
suggested_experiments:
- hypothesis: ROR1 transduces Wnt5a signals independently of any kinase activity.
  description: Compare Wnt5a-dependent signaling/migration in cells expressing wild-type ROR1 vs an extracellular-CRD
    mutant that cannot bind Wnt.