ROS1 is a large single-pass type I transmembrane receptor tyrosine kinase with an extensive extracellular region of fibronectin type III repeats and an intracellular kinase domain. It was long an orphan receptor; NELL2 is an endogenous ligand, and NELL2-ROS1 signalling drives regionalized differentiation of the proximal epididymal epithelium and consequent sperm maturation, which is why Ros1-null male mice are infertile. Activated ROS1 autophosphorylates and phosphorylates substrates including PTPN11/SHP-2 and the guanine nucleotide exchange factor VAV3, engaging PI3K-AKT-mTOR, MAPK/ERK and STAT3 signalling to control cell growth, differentiation and survival; phosphotyrosines in its activation loop and tail also recruit the phosphatases PTPN6 and PTPN11. ROS1 is expressed in brain and epididymal epithelium, and chromosomal rearrangements that fuse its kinase domain to partners such as FIG/GOPC, CD74 or SLC34A2 produce constitutively active, often cytoplasmic oncoproteins that drive glioblastoma, lung adenocarcinoma and other cancers and are targets of ROS1 kinase inhibitors.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001558 regulation of cell growth | IDA PMID:16885344 ROS fusion tyrosine kinase activates a SH2 domain-containing... | KEEP AS NON CORE | Summary: ROS1 signalling regulates cell growth. Reason: Growth control is a downstream consequence of ROS1-driven PI3K-mTOR and STAT3 signalling rather than a distinct activity. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt May also phosphorylate and activate the transcription factor STAT3 to control anchorage-independent cell growth. |
| GO:0002066 columnar/cuboidal epithelial cell development | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ROS1 is required for differentiation of epididymal columnar epithelium. Reason: A genuine, well-documented role transferred from mouse; it is a tissue-specific developmental output of the receptor signalling function. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt Receptor tyrosine kinase (RTK) that plays a role in epithelial cell differentiation and regionalization of the proximal epididymal epithelium. |
| GO:0004672 protein kinase activity | IEA GO_REF:0000002 | MODIFY | Summary: Generic protein kinase activity from InterPro kinase signatures. Reason: Correct but too general; ROS1 is a tyrosine-specific receptor kinase, terms already carried by this gene with experimental evidence. Proposed replacements: protein tyrosine kinase activity transmembrane receptor protein tyrosine kinase activity |
| GO:0004713 protein tyrosine kinase activity | EXP PMID:11094073 Vav3 mediates receptor protein tyrosine kinase signaling, re... | ACCEPT | Summary: ROS1 phosphorylates tyrosine residues on substrate proteins. Reason: ROS1 autophosphorylates and phosphorylates VAV3 and PTPN11; UniProt records EC 2.7.10.1 with experimental evidence. Supporting Evidence: PMID:11094073 ligand stimulation of several RPTKs (epidermal growth factor receptor [EGFR], Ros, insulin receptor [IR], and insulin-like growth factor I receptor [IGFR]) led to tyrosine phosphorylation of Vav3 file:human/ROS1/ROS1-uniprot.txt Mediates the phosphorylation of PTPN11, an activator of this pathway. |
| GO:0004713 protein tyrosine kinase activity | IDA PMID:16885344 ROS fusion tyrosine kinase activates a SH2 domain-containing... | ACCEPT | Summary: ROS1 phosphorylates tyrosine residues on substrate proteins. Reason: ROS1 autophosphorylates and phosphorylates VAV3 and PTPN11; UniProt records EC 2.7.10.1 with experimental evidence. Supporting Evidence: PMID:11094073 ligand stimulation of several RPTKs (epidermal growth factor receptor [EGFR], Ros, insulin receptor [IR], and insulin-like growth factor I receptor [IGFR]) led to tyrosine phosphorylation of Vav3 file:human/ROS1/ROS1-uniprot.txt Mediates the phosphorylation of PTPN11, an activator of this pathway. |
| GO:0004713 protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: ROS1 phosphorylates tyrosine residues on substrate proteins. Reason: ROS1 autophosphorylates and phosphorylates VAV3 and PTPN11; UniProt records EC 2.7.10.1 with experimental evidence. Supporting Evidence: PMID:11094073 ligand stimulation of several RPTKs (epidermal growth factor receptor [EGFR], Ros, insulin receptor [IR], and insulin-like growth factor I receptor [IGFR]) led to tyrosine phosphorylation of Vav3 file:human/ROS1/ROS1-uniprot.txt Mediates the phosphorylation of PTPN11, an activator of this pathway. |
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | IBA GO_REF:0000033 | ACCEPT | Summary: ROS1 is a transmembrane receptor tyrosine kinase. Reason: A single-pass receptor with a large extracellular region and an intracellular kinase domain that is activated by the ligand NELL2 and signals from the cell surface. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt Upon endogenous stimulation by NELL2, ROS1 activates the intracellular signaling pathway file:human/ROS1/ROS1-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Single-pass type I membrane protein |
| GO:0004714 transmembrane receptor protein tyrosine kinase activity | IEA GO_REF:0000120 | ACCEPT | Summary: ROS1 is a transmembrane receptor tyrosine kinase. Reason: A single-pass receptor with a large extracellular region and an intracellular kinase domain that is activated by the ligand NELL2 and signals from the cell surface. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt Upon endogenous stimulation by NELL2, ROS1 activates the intracellular signaling pathway file:human/ROS1/ROS1-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Single-pass type I membrane protein |
| GO:0005515 protein binding | IPI PMID:17416557 Monitoring phosphatase reactions of multiple phosphorylated ... | REMOVE | Summary: Generic protein binding from peptide-dephosphorylation and interaction studies. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The informative interaction - with the phosphatases that act on its activation-loop phosphotyrosines - is captured by protein phosphatase binding. |
| GO:0005515 protein binding | IPI PMID:17416557 Monitoring phosphatase reactions of multiple phosphorylated ... | REMOVE | Summary: Generic protein binding from peptide-dephosphorylation and interaction studies. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The informative interaction - with the phosphatases that act on its activation-loop phosphotyrosines - is captured by protein phosphatase binding. |
| GO:0005515 protein binding | IPI PMID:32499443 NELL2-mediated lumicrine signaling through OVCH2 is required... | REMOVE | Summary: Generic protein binding from peptide-dephosphorylation and interaction studies. Reason: GO:0005515 is uninformative and removed under the project protein-binding policy. The informative interaction - with the phosphatases that act on its activation-loop phosphotyrosines - is captured by protein phosphatase binding. |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | ACCEPT | Summary: ROS1 binds ATP as its phosphate donor. Reason: Follows directly from the demonstrated tyrosine kinase activity and the conserved kinase fold; ATP-competitive inhibitors of ROS1 are clinically used. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt Reaction=L-tyrosyl-[protein] + ATP = O-phospho-L-tyrosyl-[protein] |
| GO:0005886 plasma membrane | IBA GO_REF:0000033 | ACCEPT | Summary: ROS1 is a single-pass type I plasma membrane receptor. Reason: The full-length receptor presents its fibronectin-repeat ectodomain at the cell surface and signals from the plasma membrane. Note that the oncogenic fusion proteins lose this anchoring and signal from intracellular membranes or the cytoplasm. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Single-pass type I membrane protein |
| GO:0005886 plasma membrane | IEA GO_REF:0000044 | ACCEPT | Summary: ROS1 is a single-pass type I plasma membrane receptor. Reason: The full-length receptor presents its fibronectin-repeat ectodomain at the cell surface and signals from the plasma membrane. Note that the oncogenic fusion proteins lose this anchoring and signal from intracellular membranes or the cytoplasm. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt SUBCELLULAR LOCATION: Cell membrane {ECO:0000305}; Single-pass type I membrane protein |
| GO:0006468 protein phosphorylation | IDA PMID:16885344 ROS fusion tyrosine kinase activates a SH2 domain-containing... | ACCEPT | Summary: ROS1 phosphorylates proteins. Reason: Direct experimental demonstration of substrate phosphorylation (PTPN11, VAV3, autophosphorylation) in human cells. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt Mediates the phosphorylation and the activation of VAV3, a guanine nucleotide exchange factor regulating cell morphology. |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | IBA GO_REF:0000033 | ACCEPT | Summary: ROS1 initiates receptor tyrosine kinase signalling from the cell surface. Reason: NELL2 binding activates the receptor, which then triggers intracellular signalling cascades; supported by phylogenetic inference and experiment. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt Upon endogenous stimulation by NELL2, ROS1 activates the intracellular signaling pathway and triggers epididymal epithelial differentiation and subsequent sperm maturation |
| GO:0007169 cell surface receptor protein tyrosine kinase signaling pathway | IEA GO_REF:0000002 | ACCEPT | Summary: ROS1 initiates receptor tyrosine kinase signalling from the cell surface. Reason: NELL2 binding activates the receptor, which then triggers intracellular signalling cascades; supported by phylogenetic inference and experiment. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt Upon endogenous stimulation by NELL2, ROS1 activates the intracellular signaling pathway and triggers epididymal epithelial differentiation and subsequent sperm maturation |
| GO:0007283 spermatogenesis | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ROS1 is required for sperm maturation through epididymal differentiation. Reason: An organismal output - ROS1 acts in the epididymal epithelium, and sperm maturation failure is the consequence, not a process ROS1 executes in germ cells. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt triggers epididymal epithelial differentiation and subsequent sperm maturation |
| GO:0016020 membrane | IEA GO_REF:0000002 | MODIFY | Summary: Generic membrane localization. Reason: Correct but too general; ROS1 is specifically a single-pass plasma membrane receptor, already annotated with more specific evidence. Proposed replacements: plasma membrane Supporting Evidence: PMID:3785223 both mcf3 and v-ros encode a potential transmembrane domain N terminal to the kinase domain |
| GO:0016020 membrane | TAS PMID:3785223 Characterization of an activated human ros gene. | MODIFY | Summary: Generic membrane localization. Reason: Correct but too general; ROS1 is specifically a single-pass plasma membrane receptor, already annotated with more specific evidence. Proposed replacements: plasma membrane Supporting Evidence: PMID:3785223 both mcf3 and v-ros encode a potential transmembrane domain N terminal to the kinase domain |
| GO:0019903 protein phosphatase binding | IEA GO_REF:0000117 | ACCEPT | Summary: ROS1 binds protein tyrosine phosphatases. Reason: Phosphorylated ROS1 recruits PTPN6/SHP-1 and PTPN11/SHP-2, which both regulate and are regulated by the receptor; this is an informative, mechanistically meaningful binding activity. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt Phosphorylation at Tyr-2274 is required for the interaction with PTPN6 |
| GO:0019903 protein phosphatase binding | IPI PMID:16885344 ROS fusion tyrosine kinase activates a SH2 domain-containing... | ACCEPT | Summary: ROS1 binds protein tyrosine phosphatases. Reason: Phosphorylated ROS1 recruits PTPN6/SHP-1 and PTPN11/SHP-2, which both regulate and are regulated by the receptor; this is an informative, mechanistically meaningful binding activity. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt Phosphorylation at Tyr-2274 is required for the interaction with PTPN6 |
| GO:0030154 cell differentiation | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ROS1 contributes to cell differentiation. Reason: Very general process term; the specific epithelial differentiation role is annotated separately and retained. |
| GO:0032006 regulation of TOR signaling | IBA GO_REF:0000033 | ACCEPT | Summary: ROS1 regulates mTOR signalling. Reason: ROS1 phosphorylates PTPN11 and thereby activates the PI3K-mTOR axis, shown directly in human cells and supported by phylogenetic inference. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. |
| GO:0032006 regulation of TOR signaling | IDA PMID:16885344 ROS fusion tyrosine kinase activates a SH2 domain-containing... | ACCEPT | Summary: ROS1 regulates mTOR signalling. Reason: ROS1 phosphorylates PTPN11 and thereby activates the PI3K-mTOR axis, shown directly in human cells and supported by phylogenetic inference. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt May activate several downstream signaling pathways related to cell differentiation, proliferation, growth and survival including the PI3 kinase-mTOR signaling pathway. |
| GO:0043235 signaling receptor complex | IBA GO_REF:0000033 | ACCEPT | Summary: ROS1 is part of a signalling receptor complex. Reason: As an activated RTK, ROS1 assembles with its ligand and with recruited SH2-domain effectors and phosphatases into a signalling complex at the membrane. Supporting Evidence: PMID:11094073 association with the receptors as well as their downstream signaling molecules, including Shc, Grb2, phospholipase C (PLC-gamma), and phosphatidylinositol 3 kinase |
| GO:0070372 regulation of ERK1 and ERK2 cascade | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: ROS1 signalling feeds into the ERK1/2 cascade. Reason: ERK activation is downstream of the receptor through adaptor and PTPN11 recruitment; modulatory rather than core. Supporting Evidence: file:human/ROS1/ROS1-uniprot.txt May activate other downstream signaling proteins including AKT1, MAPK1, MAPK3, IRS1 and PLCG2. |
| GO:1902531 regulation of intracellular signal transduction | IEA GO_REF:0000117 | TOO GENERAL | Summary: Regulation of intracellular signal transduction. Reason: True but uninformative; the specific terms for receptor tyrosine kinase signalling, protein phosphorylation and regulation of TOR signalling asserted in this review entail it. |
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Download this section (compressed HTML)Q: Does NELL2 activate human ROS1 in tissues other than the epididymis, and are there additional ligands for the very large fibronectin-repeat ectodomain?
Q: Where do the common ROS1 fusion oncoproteins actually signal from, and how does losing the transmembrane anchor change the substrate repertoire relative to full-length receptor?
Q: What is the physiological role of ROS1 in human brain, where it is expressed and upregulated in glioma?
Experiment: Phosphoproteomics of isogenic cells expressing full-length NELL2-stimulated ROS1 versus a FIG-ROS1 or CD74-ROS1 fusion, to compare substrate sets and identify fusion-specific signalling.
Experiment: Ligand-binding and cell-surface receptor activation assays with recombinant NELL2 on human epithelial cells expressing full-length ROS1, establishing the human (not only mouse) ligand-receptor relationship quantitatively.
Experiment: Conditional ROS1 loss in human epididymal or airway epithelial organoids, assaying regional differentiation markers and PI3K-mTOR pathway output.
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