Affinage

Showing MST1R — RON is a alias.

MST1R

Macrophage-stimulating protein receptor · UniProt Q04912

Length
1400 aa
Mass
152.2 kDa
Annotated
2026-06-10
100 papers in source corpus 32 papers cited in narrative 32 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MST1R (RON) is a heterodimeric receptor tyrosine kinase whose intracellular β-chain is activated by the HGF-homologue MSP, driving epithelial DNA synthesis, migration, proliferation, and survival (PMID:8062829, PMID:7939629). Ligand binding requires the receptor sema domain, and a soluble sema fragment acts as a dominant-negative antagonist (PMID:14597639). Activated RON couples to a branched signaling network — FAK, c-Src/MAPK, JNK, and PI3K/AKT — in which c-Src/MAPK and FAK drive proliferation while PI3K/AKT confers anti-apoptotic and motility outputs (PMID:10080538, PMID:18836480), and engages the β-catenin/Tcf axis to induce c-myc and cyclin D1 during oncogenic transformation (PMID:11486025). RON cooperates with other receptor tyrosine kinases: it forms non-covalent surface complexes with MET enabling bidirectional transphosphorylation, and RON transactivation contributes to MET oncogene addiction (PMID:10871856, PMID:21212418); it also physically associates with and is transphosphorylated by EGFR and IGF-1R (PMID:14499632, PMID:21565828). Oncogenic point mutations and constitutively active truncated/spliced isoforms (sf-RON, P5P6, RONΔ165) signal ligand-independently through AKT and repress E-cadherin via SLUG to drive EMT and tumorigenesis (PMID:11593422, PMID:15289319, PMID:26477314, PMID:32669614), and RON/MSP promotes metastasis through a PI3K→MBD4 epigenetic reprogramming pathway requiring MBD4 glycosylase activity (PMID:24388747). Under hypoxia, RON translocates to the nucleus, interacts with HIF-1α, and directly activates c-JUN transcription in a kinase-dependent manner (PMID:24903148). In macrophages, MSP/RON signaling is broadly immunosuppressive: it induces SOCS1 to inhibit IFN-γ/STAT1 responses (PMID:18684919), blocks NF-κB- and Adam17-dependent TNF-α production (PMID:19487969, PMID:21520175), upregulates arginase I via an AP-1/Fos mechanism (PMID:21810604), and modulates CD80/PD-L1 surface expression to restrain antitumor immunity (PMID:30228950). RON additionally activates osteoclasts through a SRC-convergent pathway driving cancer-associated bone destruction (PMID:28123075).

Mechanistic history

Synthesis pass · year-by-year structured walk · 27 steps
  1. 1994 High

    Established RON as a bona fide receptor tyrosine kinase and identified MSP as its specific ligand, defining the core receptor-ligand axis distinct from the HGF/MET system.

    Evidence Immunoprecipitation, in vitro kinase assay, radioligand cross-linking, and reciprocal ligand-specificity controls in transfected epithelial cells

    PMID:7939629 PMID:8062829

    Open questions at the time
    • Downstream effector cascades not yet mapped
    • Physiological tissue contexts unaddressed
  2. 1998 Medium

    Defined the genomic structure and transcriptional control elements of the Ron gene, providing the basis for understanding context-specific expression.

    Evidence Genomic library screening, deletion-reporter CAT assays, and gel mobility shift assays of mouse promoter regions

    PMID:9467940

    Open questions at the time
    • Specific trans-acting transcription factors not identified
    • Human promoter not characterized in this study
  3. 1999 Medium

    Resolved the branched intracellular signaling architecture downstream of RON, separating proliferative from survival and motility outputs.

    Evidence In vitro kinase assays with pharmacological inhibitors and dominant-negative constructs across MSP time-courses

    PMID:10080538

    Open questions at the time
    • Direct adaptor docking events not mapped
    • Single-lab pathway dissection
  4. 2001 High

    Showed that oncogenic RON mutants transform cells and metastasize, and that β-catenin/Tcf is a required downstream oncogenic effector, linking RON activation to transcriptional programs.

    Evidence Oncogenic mutant transfection, β-catenin phosphorylation, Tcf reporter assays, NIH3T3 transformation, and in vivo metastasis models

    PMID:11486025 PMID:11593422

    Open questions at the time
    • Mechanism of β-catenin tyrosine phosphorylation not defined
    • Relevance of specific mutations to human tumors not established
  5. 2000 High

    Demonstrated that RON and MET form surface complexes with bidirectional transphosphorylation, establishing cross-talk within the scatter-factor receptor subfamily.

    Evidence Kinase-inactive mutants, cell-surface cross-linking, phosphosite mapping, and dominant-negative focus-formation assays

    PMID:10871856

    Open questions at the time
    • Stoichiometry of MET-RON complexes not defined
    • In vivo relevance not addressed in this study
  6. 2002 Medium

    Identified the immunoregulatory anti-apoptotic role of RON in macrophages, mediated by PI3K-dependent suppression of NO and p53.

    Evidence Primary macrophage apoptosis assays with wortmannin and dominant-negative PI3K p85

    PMID:11818458

    Open questions at the time
    • Direct PI3K recruitment site on RON not mapped
    • Single-lab finding
  7. 2004 Medium

    Showed that constitutively active truncated sf-RON drives EMT through SLUG-mediated E-cadherin repression, revealing how aberrant RON isoforms produce aggressive phenotypes.

    Evidence Retroviral transduction, kinase assays, morphological and anchorage-independent growth assays with SLUG analysis

    PMID:15289319

    Open questions at the time
    • Mechanism of SLUG induction by RON not defined
    • Single-lab study
  8. 2004 Medium

    Placed RON downstream of the erythropoietin receptor in erythroid progenitor expansion via constitutive Gab1 association, broadening RON's physiological signaling partnerships.

    Evidence Co-IP, phosphorylation assays, EpoR epistasis, and ex vivo progenitor expansion assays

    PMID:14982882

    Open questions at the time
    • Direct physical EpoR-RON interaction not shown
    • Differentiation block mechanism unexplained
  9. 2008 High

    Defined RON-mediated suppression of IFN-γ/STAT1 responses via SOCS1 induction, with genetic epistasis confirming the immunosuppressive output in vivo.

    Evidence Primary macrophage STAT1/CIITA assays, SOCS1 induction, and RON/IFN-γR double-knockout rescue

    PMID:18684919

    Open questions at the time
    • Mechanism linking RON kinase to SOCS1 transcription not defined
    • Human macrophage relevance not tested
  10. 2008 Medium

    Revealed ligand-independent RON signaling modes (survival, spreading) mediated by Src family kinases, distinguishing them from MSP-dependent proliferation and migration.

    Evidence RON overexpression in MCF-10A cells with Src inhibition and phenotypic assays with/without MSP

    PMID:18836480

    Open questions at the time
    • Source of MSP-independent activation not defined
    • Single isogenic system
  11. 2008 Medium

    Identified RON as a repressor of HIV-1 transcription operating at NF-κB recruitment and Pol II elongation checkpoints, an unexpected transcriptional regulatory role.

    Evidence ChIP for Pol II and elongation factors at the HIV LTR, HDAC inhibitor treatment, and nucleosome remodeling analysis

    PMID:18209063

    Open questions at the time
    • Direct nuclear role of RON in this repression not established
    • Single-lab mechanism
  12. 2009 Medium

    Characterized a soluble antagonist isoform (RONΔ90) generated by exon skipping, demonstrating endogenous negative regulation of RON activation.

    Evidence RT-PCR, cDNA cloning, recombinant protein, and phosphorylation/migration inhibition assays

    PMID:19519771

    Open questions at the time
    • In vivo abundance and regulation of RONΔ90 unknown
    • Single-lab study
  13. 2009 Medium

    Linked RON to tumor angiogenesis through NF-κB-driven angiogenic chemokine production in prostate cancer.

    Evidence shRNA knockdown and overexpression, NF-κB assays, chemokine ELISA, endothelial chemotaxis, and orthotopic microvessel density

    PMID:19838218

    Open questions at the time
    • Direct RON-to-NF-κB signaling intermediates not mapped
    • Single-lab study
  14. 2010 High

    Mapped RON-induced arginase I expression to an AP-1/Fos promoter mechanism driving M2-like macrophage polarization and tumor growth in vivo.

    Evidence Arg1 promoter analysis, Fos ChIP at the AP-1 site, MAPK assays, and Ron(-/-) tumor models

    PMID:21810604

    Open questions at the time
    • Stat6-independence mechanism not fully resolved
    • Human tumor-associated macrophage data limited
  15. 2010 Medium

    Established RON as a negative regulator of TNF-α production and shedding in alveolar macrophages via NF-κB/IκB and Adam17 control.

    Evidence Primary alveolar macrophage NF-κB assays, IκB Western, and Adam17 expression analysis

    PMID:19487969

    Open questions at the time
    • Mechanism of Adam17 downregulation not defined
    • Single-lab study
  16. 2010 Medium

    Identified RON as an upstream activator of mutant PI3K in colon cancer, with knockdown sensitizing cells to apoptosis and reducing metastasis.

    Evidence siRNA knockdown, PI3K activity and AKT assays, apoptosis assays, and orthotopic metastasis models in PIK3CA-mutant cells

    PMID:19224914

    Open questions at the time
    • Direct RON-PI3K coupling mechanism not defined
    • Single-lab study
  17. 2010 High

    Dissected opposing cell-type-specific roles of RON in liver injury using conditional knockouts, showing hepatocyte versus Kupffer cell contributions.

    Evidence Hepatocyte- and macrophage-specific Cre deletion, conditioned-media transfer, and in vivo liver injury models

    PMID:21520175

    Open questions at the time
    • Molecular basis of divergent cell-type outputs not fully defined
  18. 2011 High

    Demonstrated that MET-addicted cancers transactivate RON, making RON a functional component of MET oncogene addiction and a co-target.

    Evidence MET-specific kinase inhibitors, antibody-induced MET shedding, RON shRNA, clonogenic assays, and xenografts

    PMID:21212418

    Open questions at the time
    • Quantitative contribution of RON to MET-driven phenotype variable
    • Single-lab study
  19. 2011 Medium

    Established unidirectional IGF-1R-to-RON transphosphorylation driving STAT3 activation and migration in pancreatic cancer.

    Evidence MudPIT proteomics, co-IP, RON shRNA/kinase inhibitor, scratch migration, and STAT3 assays

    PMID:21565828

    Open questions at the time
    • Structural basis of IGF-1R-RON interaction not defined
    • Single-lab study
  20. 2011 Medium

    Showed EBV LMP1 drives RON expression via NF-κB binding to the RON promoter, supporting B-cell transformation, linking viral oncogenesis to RON.

    Evidence NF-κB promoter binding, LMP1 CTAR1 mapping, shRNA, and knockdown-rescue proliferation assays

    PMID:21659546

    Open questions at the time
    • Direct NF-κB binding site not finely mapped
    • Single-lab study
  21. 2012 Medium

    Identified a RON-plectin-ITGB4 complex whose MSP-induced disruption of hemidesmosome anchoring promotes PI3K-dependent migration.

    Evidence MudPIT, co-IP, shRNA, migration assays, and PI3K/MEK inhibition in pancreatic cancer cells

    PMID:22275185

    Open questions at the time
    • Stoichiometry and direct contacts within the complex not defined
    • Single-lab study
  22. 2014 High

    Defined a PI3K→MBD4 epigenetic reprogramming pathway as a mechanistic driver of RON/MSP-mediated metastasis, with MBD4 glycosylase activity required.

    Evidence shRNA, MBD4 catalytic mutant rescue, methylation profiling, PI3K inhibition, and PDX in vivo metastasis models

    PMID:24388747

    Open questions at the time
    • Mechanism by which MBD4 produces locus-specific methylation changes not resolved
  23. 2014 High

    Revealed a non-canonical nuclear function for RON under hypoxia, interacting with HIF-1α and directly activating c-JUN transcription in a kinase-dependent manner.

    Evidence Cell fractionation, co-IP, c-JUN promoter ChIP, kinase-dead mutant, reporter, and hypoxic functional assays

    PMID:24903148

    Open questions at the time
    • Mechanism of RON nuclear translocation not defined
    • Single-lab study
  24. 2015 Medium

    Characterized the constitutively active P5P6 splice isoform lacking the first IPT domain, demonstrating AKT-driven transformation and tumorigenicity.

    Evidence RT-PCR, MS peptide confirmation, fractionation, kinase inhibitor, NIH3T3 transformation, and in vivo tumor formation

    PMID:26477314

    Open questions at the time
    • Mechanism of constitutive activation upon IPT loss not defined
    • Single-lab study
  25. 2017 High

    Established RON signaling in osteoclast precursors as a SRC-convergent, RANKL-complementary driver of cancer-mediated bone destruction with clinical biomarker support.

    Evidence Genetic and pharmacological RON inhibition across multiple mouse osteolysis models with clinical bone-turnover biomarker data

    PMID:28123075

    Open questions at the time
    • Direct osteoclast RON effectors beyond SRC convergence not mapped
  26. 2018 High

    Linked macrophage RON activation to immune checkpoint regulation, showing RON inhibition synergizes specifically with anti-CTLA-4 for tumor eradication.

    Evidence Flow cytometry of CD80/PD-L1, genetic/pharmacological RON inhibition, orthotopic tumors, and combination immunotherapy

    PMID:30228950

    Open questions at the time
    • Mechanism of selectivity for anti-CTLA-4 over anti-PD-1 not resolved
  27. 2020 Medium

    Identified HNRNPA2B1 as the splicing factor producing the pro-EMT RONΔ165 isoform via exon 11 exclusion, connecting alternative splicing to AKT-driven EMT.

    Evidence CRISPR/Cas9 knockout, minigene splicing reporter, EMT marker analysis, and rescue overexpression

    PMID:32669614

    Open questions at the time
    • Regulation of HNRNPA2B1 in tumors not addressed
    • Single-lab study

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the diverse RON-activating inputs (MSP, MET/EGFR/IGF-1R transactivation, hypoxia-induced nuclear translocation, constitutive splice isoforms) are integrated and selectively coupled to distinct downstream programs in a given cell type remains unresolved.
  • No unified model of input-output specificity
  • Structural basis of RON nuclear translocation and isoform constitutive activation undefined
  • Mechanism connecting RON kinase output to specific transcriptional/epigenetic effectors incompletely mapped

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0001618 virus receptor activity 2 GO:0048018 receptor ligand activity 2 GO:0140110 transcription regulator activity 1
Localization
GO:0005886 plasma membrane 4 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 4 R-HSA-162582 Signal Transduction 3 R-HSA-1643685 Disease 3 R-HSA-74160 Gene expression (Transcription) 2
Partners
EGFRGAB1HIF1AHNRNPA2B1IGF1RITGB4METPLEC
Complex memberships
MET-RON receptor complexRON-plectin-ITGB4 complex

Evidence

Reading pass · 32 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1994 RON is a heterodimeric receptor tyrosine kinase: the single-chain precursor is glycosylated, cleaved into a 185 kDa disulfide-linked heterodimer (35 kDa alpha + 150 kDa beta chains), and the beta-chain displays intrinsic tyrosine kinase activity in vitro. MSP (macrophage stimulating protein), a HGF homologue, specifically activates RON by inducing tyrosine phosphorylation, leading to DNA synthesis in epithelial cells. HGF does not activate RON, nor does MSP activate the HGF receptor. Immunoprecipitation, in vitro kinase assay, ligand stimulation assays, biochemical cross-reactivity experiments The EMBO journal High 8062829
1994 The RON gene product is confirmed as the specific cell-surface receptor for MSP: 125I-MSP cross-links to a 220 kDa complex (MSP + RON beta chain) in RON-transfected MDCK cells, MSP binding is competed by unlabeled MSP but not by HGF-SF, MSP induces phosphorylation of the RON beta chain, and triggers cell migration. Radioligand binding, chemical cross-linking, immunoprecipitation, cell migration assay Science High 7939629
2000 MET and RON receptors form non-covalent complexes on the cell surface and undergo direct transphosphorylation: ligand-activated MET transphosphorylates RON (and vice versa) at both kinase-activating tyrosines (Y1238/Y1239 in RON) and signal transducer docking sites (Y1353/Y1360 in RON). This cross-talk is restricted to the scatter factor receptor subfamily and does not occur with ErbB1, ErbB2, or TrkA. A kinase-inactive RON acts as a dominant negative suppressor of oncogenic MET mutants. Kinase-inactive mutant receptor expression, cell-surface cross-linking, phosphorylation site mapping, focus-formation transformation assay Oncogene High 10871856
2001 Oncogenic mutants of RON cause tyrosine phosphorylation and accumulation of beta-catenin, constitutive activation of Tcf transcription factor, and increased c-myc and cyclin D1 expression. Interference with the beta-catenin pathway reduces the transforming potential of mutant RON, establishing beta-catenin/Tcf as a downstream oncogenic signaling pathway of RON. Transfection of oncogenic RON mutants, beta-catenin tyrosine phosphorylation assay, Tcf luciferase reporter, Western blot, dominant-negative pathway interference Molecular and cellular biology High 11486025
2001 Point mutations in RON analogous to oncogenic MET mutations (hereditary papillary renal carcinoma) result in constitutive RON phosphorylation, cellular transformation in NIH3T3 cells, in vivo tumor formation, and lung metastasis in experimental metastasis models. Site-directed mutagenesis, NIH3T3 transformation assay, in vivo tumor formation, experimental metastasis model Oncogene High 11593422
2003 The sema domain of RON participates in MSP ligand binding by the full-length receptor. A soluble secreted sema domain fragment (ron-sema) exerts a dominant negative effect on MSP-induced RON activation, inhibiting downstream signaling pathways and MSP-dependent cellular responses including proliferation. Soluble sema domain expression, dominant-negative phosphorylation assay, cell proliferation assay The Journal of biological chemistry Medium 14597639
2003 RON and EGFR physically associate (co-immunoprecipitate) in NIH3T3 cells; ligand stimulation of either RON (with HGFL) or EGFR (with EGF) induces phosphorylation of both receptors. Dominant-negative EGFR suppresses RON-induced cell scatter, and dominant-negative RON suppresses EGFR-induced focus formation, establishing functional cross-talk between these heterologous RTKs. Co-immunoprecipitation, Western phosphorylation assay, dominant-negative co-transfection, cell scatter assay, focus formation assay Experimental cell research Medium 14499632
2004 A truncated RON variant (sf-RON) lacking most of the extracellular domain but retaining the transmembrane and intracellular domains is constitutively phosphorylated and has strong intrinsic tyrosine kinase activity. Epithelial cells transduced with sf-RON lose E-cadherin expression through a dominant transcriptional repression pathway mediated by the transcription factor SLUG, inducing EMT and an aggressive phenotype. Retroviral transduction, Western blot, kinase assay, morphological analysis, anchorage-independent growth, SLUG expression analysis Cancer research Medium 15289319
1999 MSP/RON signaling activates multiple distinct intracellular kinase pathways: FAK, c-Src, AKT, MAPK, and JNK are rapidly activated by MSP. MAPK and c-Src operate in one cascade (MAPK downstream of c-Src) mediating cell proliferation; FAK mediates proliferation via a separate pathway; PI3K/AKT mediates anti-apoptotic effects; PI3K regulates adhesion and motility via AKT-independent downstream components. In vitro kinase assays, pharmacological inhibition, dominant-negative expression, MSP stimulation time-course Journal of leukocyte biology Medium 10080538
2004 RON functions downstream of the erythropoietin receptor (EpoR) in erythroid progenitor expansion: Gab1 is constitutively associated with RON; EPO activates RON, which phosphorylates Gab1, MAPK, and PKB/AKT (but not STAT5). RON activation is sufficient to replace EPO in progenitor expansion but not in differentiation. Co-immunoprecipitation, phosphorylation assays, EPO receptor signaling epistasis, ex vivo erythroid progenitor expansion assay Blood Medium 14982882
2008 RON activation by MSP inhibits IFN-γ-induced STAT1 phosphorylation and CIITA expression in macrophages, reducing surface MHC class II levels. MSP/RON signaling induces suppressor of cytokine signaling 1 (SOCS1), providing a mechanistic explanation for RON-mediated inhibition of IFN-γ responses. In RON(-/-) mice, the enhanced susceptibility to LPS challenge is dependent on IFN-γ signaling (shown by RON/IFN-γR double knockout rescue). Primary macrophage stimulation, STAT1 phosphorylation assay, CIITA expression analysis, SOCS1 induction, genetic epistasis with double-knockout mice Journal of immunology High 18684919
2010 RON activation by MSP induces arginase I (Arg1) expression in macrophages through an AP-1 site located 433 bp upstream of the Arg1 transcription start site, via MAPK activation, Fos upregulation, and Fos binding to the AP-1 site. This mechanism is Stat6-independent. In vivo, Arg1 expression in tumor-associated macrophages is reduced in Ron(-/-) mice and is associated with reduced syngeneic tumor growth. Arg1 promoter analysis, chromatin immunoprecipitation (Fos binding to AP-1), MAPK activation assay, Ron(-/-) mouse model, tumor growth assay Journal of immunology High 21810604
2010 RON negatively regulates TNF-alpha production in alveolar macrophages by inhibiting NF-κB activation and increasing IκB levels following LPS challenge. RON activation also negatively regulates Adam17 (the metalloprotease responsible for TNF-alpha processing), establishing RON as a regulator of both TNF-alpha production and shedding. Primary alveolar macrophage stimulation, NF-κB activity assay, IκB Western blot, Adam17 expression analysis, MH-S alveolar macrophage cell line Shock Medium 19487969
2011 In MET-amplified and MET-addicted cancer cells, activated MET specifically transphosphorylates RON kinase. RON phosphorylation is suppressed by MET-specific kinase inhibitors (PHA-665752 or JNJ-38877605) or by antibody-induced shedding of cell-surface MET. shRNA silencing of RON in MET-addicted cells decreases proliferation, clonogenic activity in vitro, and tumorigenicity in vivo, establishing RON transactivation as a component of MET oncogene addiction. Phosphorylation assays, MET-specific kinase inhibitors, antibody-induced MET shedding, shRNA knockdown, in vitro clonogenic assay, in vivo xenograft Cancer research High 21212418
2010 RON signaling in macrophages suppresses LPS-induced TNF-α production while in hepatocytes it inhibits cell survival. Conditional Ron deletion studies show: Ron loss in hepatocytes leads to less liver damage and increased survival, whereas Ron loss in macrophages leads to increased cytokine production that is toxic to hepatocytes. TK(-/-) Kupffer cells produce more TNF-α after LPS, and conditioned media from these cells is more hepatotoxic. Cell-type-specific conditional Ron deletion (hepatocyte- and macrophage-specific Cre), purified primary cell cultures, conditioned media transfer assay, in vivo liver injury model Hepatology High 21520175
2012 RON interacts with plectin and integrin-β4 (ITGB4) in pancreatic cancer cells. Upon MSP stimulation, RON binds to plectin and ITGB4, disrupting the plectin-ITGB4 interaction that normally anchors hemidesmosomes to the extracellular matrix. This disruption enhances cell migration in a manner dependent on RON and PI3K activity, but not MEK. Multidimensional protein identification analysis (MudPIT), co-immunoprecipitation, shRNA knockdown, cell migration assay, pharmacological PI3K/MEK inhibition International journal of cancer Medium 22275185
2011 IGF-1R physically interacts with RON in pancreatic cancer cells. IGF-1 induces rapid phosphorylation of RON, but RON signaling does not activate IGF-1R (unidirectional signaling). IGF-1-induced pancreatic cancer cell migration is RON-dependent: shRNA knockdown of RON or RON kinase inhibitor abrogates IGF-1-induced wound closure. In pancreatic cancer cells, IGF-1 activates STAT3 in a RON-dependent manner. MudPIT proteomics, co-immunoprecipitation, shRNA knockdown, kinase inhibitor, scratch wound migration assay, STAT3 phosphorylation assay Carcinogenesis Medium 21565828
2014 RON/MSP signaling promotes breast cancer metastasis through an epigenetic reprogramming pathway: via PI3K signaling, RON/MSP induces expression of the DNA glycosylase MBD4, which drives aberrant DNA methylation at specific loci misregulating a defined gene set. MBD4 glycosylase catalytic activity is required for RON/MSP-driven metastasis. Knockdown of MBD4 reverses methylation and blocks metastasis. shRNA knockdown, MBD4 catalytic mutant rescue, methylation profiling, PI3K inhibition, in vivo metastasis assay, patient-derived xenograft pharmacological RON inhibition Cell reports High 24388747
2009 A novel soluble RON splice variant (RONDelta90), generated by skipping exon 6 causing a frameshift and premature termination in exon 7, is secreted as a truncated soluble protein. RONDelta90 inhibits MSP-induced phosphorylation of full-length cellular RON, attenuates basal RON activation, and inhibits MSP-induced glioma cell migration and random motility, functioning as an endogenous antagonist. RT-PCR, cDNA cloning, recombinant protein expression and purification, RON phosphorylation inhibition assay, cell migration assay Journal of neurochemistry Medium 19519771
2008 RON promotes MSP-independent cell survival, increased cell spreading, and enhanced migration in response to other growth factors when expressed in MCF-10A breast epithelial cells. Both MSP-dependent and MSP-independent RON signaling are mediated in part by Src family kinases. RON-mediated proliferation and directional migration require MSP, but survival and spreading do not. RON overexpression in MCF-10A cells, Src family kinase inhibition, cell survival assay, spreading assay, migration assay with/without MSP Oncogene Medium 18836480
2014 Under hypoxic conditions, RON translocates to the nucleus of cancer cells. Nuclear RON interacts with HIF-1α in a manner dependent on RON tyrosine kinase activity, binds the c-JUN promoter, and activates c-JUN transcription. Nuclear RON plays a more important role than HIF-1α in c-JUN promoter activation, promoting cancer cell survival, proliferation, and tumorigenicity under hypoxia. Cell fractionation, co-immunoprecipitation of nuclear RON with HIF-1α, chromatin immunoprecipitation at c-JUN promoter, kinase-dead mutant, reporter assay, functional proliferation/survival assays under hypoxia Cancer research High 24903148
2008 RON represses HIV-1 transcription at multiple checkpoints: RON expression decreases NF-κB and RNA Pol II binding to the HIV LTR, reduces RNA Pol II processivity at sequences downstream of the transcription start site, and increases binding of negative elongation factors NELF, Spt5, and Pcf11. RON-mediated repression is sensitive to HDAC inhibition and is associated with nucleosome remodeling. Chromatin immunoprecipitation (ChIP) for transcription factors and Pol II at HIV LTR, elongation factor binding assay, HDAC inhibitor treatment, nucleosome remodeling analysis Journal of immunology Medium 18209063
2002 RON activation by MSP inhibits LPS-induced apoptosis of macrophages by suppressing nitric oxide production and p53 accumulation. The anti-apoptotic effect of RON requires PI3K activity, as demonstrated by wortmannin inhibition and dominant-negative PI3K p85 subunit expression. Primary peritoneal macrophage assay, NO measurement, p53 Western blot, wortmannin pharmacological inhibition, dominant-negative PI3K p85 expression, apoptosis assay Journal of leukocyte biology Medium 11818458
2011 EBV latent membrane protein 1 (LMP1) enhances RON expression through its C-terminal activation region-1 (CTAR1) by promoting NF-κB binding to the RON promoter. RON is expressed in EBV-transformed lymphoblastoid cell lines (LCLs) but not primary B cells; RON knockdown decreases LCL proliferation, and RON re-expression compensates for growth inhibition caused by LMP1 knockdown. NF-κB binding to RON promoter assay, LMP1 CTAR1 domain mapping, shRNA knockdown, rescue overexpression, proliferation assay Blood Medium 21659546
2020 The splicing factor HNRNPA2B1 mediates exclusion of cassette exon 11 from MST1R pre-mRNA, producing the RON∆165 isoform. CRISPR/Cas9 knockout of HNRNPA2B1 reduces RON∆165 production (confirmed by minigene assay), decreases Akt/PKB signaling, upregulates E-cadherin and downregulates vimentin, reducing EMT. HNRNPA2B1 overexpression in KO cells rescues RON∆165 expression and restores Akt activation and EMT. CRISPR/Cas9 knockout, minigene splicing reporter assay, Western blot, EMT marker analysis, rescue overexpression Laboratory investigation Medium 32669614
2017 MSP signals through RON expressed on osteoclast precursors to activate osteoclasts by a pathway complementary to RANKL signaling and converging on SRC kinase. Genetic or pharmacological inhibition of RON kinase blocks cancer-mediated bone destruction and osteoporosis in multiple mouse models. Clinical trial data show that a RON kinase inhibitor (BMS-777607/ASLAN002) alters markers of bone turnover in cancer patients. Genetic RON deletion, pharmacological RON inhibition, multiple mouse osteolysis models, SRC pathway analysis, clinical biomarker analysis Science translational medicine High 28123075
2018 RON activation by MSP in macrophages upregulates surface levels of CD80 and PD-L1 (ligands for CTLA-4 and PD-1 on T cells). Genetic deletion or pharmacological inhibition of RON combined with anti-CTLA-4 (but not anti-PD-1) results in complete tumor eradication in ~46% of animals, associated with higher T-cell activation and tumor-infiltrating lymphocytes. Flow cytometry for CD80/PD-L1 surface expression, genetic Ron deletion, pharmacological inhibition, orthotopic tumor transplantation, combination immunotherapy study, T-cell activation markers Oncoimmunology High 30228950
2010 RON knockdown in HCT116 colon cancer cells (heterozygous for PIK3CA H1047R gain-of-function mutation) reduces mutant PI3K activity and AKT phosphorylation, sensitizes cells to growth factor deprivation-induced apoptosis, and significantly reduces lung metastasis in orthotopic models. This establishes RON as an upstream activator of mutant PI3K in colon cancer. siRNA knockdown, PI3K activity assay, AKT phosphorylation, caspase-3/DNA fragmentation apoptosis assay, orthotopic metastasis model The Journal of biological chemistry Medium 19224914
2007 MSP stimulation of pancreatic cancer cells results in increased phosphorylation of MAPK and AKT via RON, promotes migration and invasion in a dose-dependent manner, and RON inhibition by monoclonal antibody reverses these effects. RON activation leads to E-cadherin loss and nuclear translocation of beta-catenin (consistent with EMT). Western blot for phospho-MAPK and phospho-AKT, migration/invasion assay, RON monoclonal antibody blockade, E-cadherin immunofluorescence, beta-catenin localization Cancer Medium 17311308
2009 RON positively regulates production of angiogenic chemokines in prostate cancer cells through NF-κB signaling. RON knockdown decreases NF-κB activation and angiogenic chemokine production; Ron overexpression in LNCaP cells increases chemokines, which can be abrogated by NF-κB inhibition. RON knockdown reduces endothelial cell chemotaxis in vitro and reduces tumor microvessel density in vivo. shRNA knockdown, NF-κB activity assay, chemokine ELISA, endothelial cell chemotaxis assay, orthotopic xenograft with microvessel density Oncogene Medium 19838218
2015 A novel RON isoform (P5P6), arising from partial splicing of exons 5 and 6 and lacking the first extracellular IPT domain, is constitutively phosphorylated, localizes to cytoplasm and traffics to plasma membrane, and activates AKT (and MAPK in some cell types). P5P6 transforms NIH3T3 cells and induces tumorigenicity in immortalized human pancreatic duct epithelial (HPDE) cells. RT-PCR, mass spectrometry peptide confirmation, Western blot, subcellular fractionation, kinase inhibitor, NIH3T3 transformation assay, in vivo tumor formation Oncogene Medium 26477314
1998 The mouse Ron gene contains 19 exons spanning ~13.2 kb. Two promoter regions (nucleotides -585 to -465 and -465 to -285) are critical for Ron expression in epithelial cells, and gel mobility shift assays indicate specific protein binding at -585 to -508 (negative regulation) and -375 to -285 (positive regulation). Genomic library screening, primer extension, deletion reporter gene constructs (CAT assay), transient transfection, gel mobility shift assay Oncogene Medium 9467940

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1994 RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. The EMBO journal 280 8062829
1994 Identification of the ron gene product as the receptor for the human macrophage stimulating protein. Science (New York, N.Y.) 243 7939629
2013 MSP-RON signalling in cancer: pathogenesis and therapeutic potential. Nature reviews. Cancer 163 23792360
2000 Cross-talk between the proto-oncogenes Met and Ron. Oncogene 159 10871856
2008 Met-related receptor tyrosine kinase Ron in tumor growth and metastasis. Advances in cancer research 138 18620091
2012 LY2801653 is an orally bioavailable multi-kinase inhibitor with potent activity against MET, MST1R, and other oncoproteins, and displays anti-tumor activities in mouse xenograft models. Investigational new drugs 133 23275061
2001 Oncogenic mutants of RON and MET receptor tyrosine kinases cause activation of the beta-catenin pathway. Molecular and cellular biology 129 11486025
2014 Plasticity and redundancy among AMA-RON pairs ensure host cell entry of Toxoplasma parasites. Nature communications 128 24934579
2011 Regulation of macrophage arginase expression and tumor growth by the Ron receptor tyrosine kinase. Journal of immunology (Baltimore, Md. : 1950) 118 21810604
2003 Oncogenic and invasive potentials of human macrophage-stimulating protein receptor, the RON receptor tyrosine kinase. Carcinogenesis 113 12807733
2007 The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression. Cancer research 105 17616662
2005 RON, a tyrosine kinase receptor involved in tumor progression and metastasis. Annals of surgical oncology 99 15827676
2003 The RON and MET oncogenes are co-expressed in human ovarian carcinomas and cooperate in activating invasiveness. Experimental cell research 99 12915129
2007 Multiple variants of the RON receptor tyrosine kinase: biochemical properties, tumorigenic activities, and potential drug targets. Cancer letters 93 17889431
2009 RNA viruses in the sea. FEMS microbiology reviews 92 19243445
2004 Truncated RON tyrosine kinase drives tumor cell progression and abrogates cell-cell adhesion through E-cadherin transcriptional repression. Cancer research 88 15289319
2007 Tyrosine kinase receptor RON in human pancreatic cancer: expression, function, and validation as a target. Cancer 86 17311308
2015 SEA: a super-enhancer archive. Nucleic acids research 84 26578594
2018 Pharmacological Potential of Sea Cucumbers. International journal of molecular sciences 83 29724051
2010 Silencing of RON receptor signaling promotes apoptosis and gemcitabine sensitivity in pancreatic cancers. Cancer research 83 20103639
2016 Rare cancers: a sea of opportunity. The Lancet. Oncology 82 26868354
2015 Biogeography of Viruses in the Sea. Annual review of virology 82 26958906
2016 Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma. Proceedings of the National Academy of Sciences of the United States of America 70 26951679
2002 Macrophage-stimulating protein and RON receptor tyrosine kinase: potential regulators of macrophage inflammatory activities. Scandinavian journal of immunology 70 12472665
2001 Point mutations and overexpression of Ron induce transformation, tumor formation, and metastasis. Oncogene 68 11593422
2005 Ron receptor signaling augments mammary tumor formation and metastasis in a murine model of breast cancer. Cancer research 67 15735014
2004 Compatible and counteracting solutes: protecting cells from the Dead Sea to the deep sea. Science progress 67 15651637
2009 From concept to reality: the long road to c-Met and RON receptor tyrosine kinase inhibitors for the treatment of cancer. Anti-cancer agents in medicinal chemistry 66 19199866
2009 Knockdown of Ron kinase inhibits mutant phosphatidylinositol 3-kinase and reduces metastasis in human colon carcinoma. The Journal of biological chemistry 65 19224914
2014 Vocal learning in seals, sea lions, and walruses. Current opinion in neurobiology 63 25042930
2011 Ron kinase transphosphorylation sustains MET oncogene addiction. Cancer research 63 21212418
2010 Synthetic lethality screens reveal RPS6 and MST1R as modifiers of insulin-like growth factor-1 receptor inhibitor activity in childhood sarcomas. Cancer research 62 20959493
2010 Ron receptor tyrosine kinase activation confers resistance to tamoxifen in breast cancer cell lines. Neoplasia (New York, N.Y.) 60 20689759
2004 RNA-mediated gene silencing of the RON receptor tyrosine kinase alters oncogenic phenotypes of human colorectal carcinoma cells. Oncogene 60 15378025
2003 Cross-talk between the receptor tyrosine kinases Ron and epidermal growth factor receptor. Experimental cell research 58 14499632
2003 Oncogenic signaling pathways activated by RON receptor tyrosine kinase. Current cancer drug targets 57 12570659
2017 RON kinase: A target for treatment of cancer-induced bone destruction and osteoporosis. Science translational medicine 55 28123075
2009 The Ron receptor tyrosine kinase positively regulates angiogenic chemokine production in prostate cancer cells. Oncogene 54 19838218
2010 The macrophage stimulating protein/Ron pathway as a potential therapeutic target to impede multiple mechanisms involved in breast cancer progression. Current drug targets 51 20545605
2011 Ron receptor regulates Kupffer cell-dependent cytokine production and hepatocyte survival following endotoxin exposure in mice. Hepatology (Baltimore, Md.) 50 21520175
2015 Roles of c-Met and RON kinases in tumor progression and their potential as therapeutic targets. Oncotarget 49 25784650
2013 Myeloid-specific expression of Ron receptor kinase promotes prostate tumor growth. Cancer research 47 23328584
2008 The RON receptor tyrosine kinase regulates IFN-gamma production and responses in innate immunity. Journal of immunology (Baltimore, Md. : 1950) 45 18684919
2012 The RON-receptor regulates pancreatic cancer cell migration through phosphorylation-dependent breakdown of the hemidesmosome. International journal of cancer 44 22275185
2014 The RON receptor tyrosine kinase promotes metastasis by triggering MBD4-dependent DNA methylation reprogramming. Cell reports 43 24388747
2009 RON receptor tyrosine kinase in human gliomas: expression, function, and identification of a novel soluble splice variant. Journal of neurochemistry 43 19519771
1999 Kinases involved in MSP/RON signaling. Journal of leukocyte biology 43 10080538
2008 Expression of the RON receptor tyrosine kinase and its association with gastric carcinoma versus normal gastric tissues. BMC cancer 42 19040718
2010 Ron receptor tyrosine kinase negatively regulates TNFalpha production in alveolar macrophages by inhibiting NF-kappaB activity and Adam17 production. Shock (Augusta, Ga.) 41 19487969
2010 Potential therapeutics specific to c-MET/RON receptor tyrosine kinases for molecular targeting in cancer therapy. Acta pharmacologica Sinica 41 20694025
2011 IGF1-R signals through the RON receptor to mediate pancreatic cancer cell migration. Carcinogenesis 39 21565828
2008 The RON receptor tyrosine kinase promotes MSP-independent cell spreading and survival in breast epithelial cells. Oncogene 39 18836480
2016 FOXC1 promotes melanoma by activating MST1R/PI3K/AKT. Oncotarget 38 27533251
2007 Ron-receptor tyrosine kinase in tumorigenesis and metastasis. Future oncology (London, England) 38 17661719
2006 Oncogenesis of RON receptor tyrosine kinase: a molecular target for malignant epithelial cancers. Acta pharmacologica Sinica 38 16723080
2003 The soluble sema domain of the RON receptor inhibits macrophage-stimulating protein-induced receptor activation. The Journal of biological chemistry 38 14597639
2022 The AMA1-RON complex drives Plasmodium sporozoite invasion in the mosquito and mammalian hosts. PLoS pathogens 36 35731833
2004 Tyrosine kinase receptor RON functions downstream of the erythropoietin receptor to induce expansion of erythroid progenitors. Blood 36 14982882
2002 Deletion of the Ron receptor tyrosine kinase domain in mice provides protection from endotoxin-induced acute liver failure. Hepatology (Baltimore, Md.) 36 12395314
2017 Library Construction from Subnanogram DNA for Pelagic Sea Water and Deep-Sea Sediments. Microbes and environments 33 29187708
2006 Collaboration of RON and epidermal growth factor receptor in human bladder carcinogenesis. The Journal of urology 33 17070309
2002 The role of the receptor tyrosine kinase Ron in nickel-induced acute lung injury. American journal of respiratory cell and molecular biology 33 11751209
2015 A novel protein isoform of the RON tyrosine kinase receptor transforms human pancreatic duct epithelial cells. Oncogene 32 26477314
2012 Differential expression of RON in small and non-small cell lung cancers. Genes, chromosomes & cancer 32 22585712
2008 Curcumin blocks RON tyrosine kinase-mediated invasion of breast carcinoma cells. Cancer research 32 18593918
2004 Expression of RON Proto-oncogene in Renal Oncocytoma and Chromophobe Renal Cell Carcinoma. The American journal of surgical pathology 32 15252311
2020 The HNRNPA2B1-MST1R-Akt axis contributes to epithelial-to-mesenchymal transition in head and neck cancer. Laboratory investigation; a journal of technical methods and pathology 31 32669614
2020 MSP-RON Pathway: Potential Regulator of Inflammation and Innate Immunity. Frontiers in immunology 31 33117355
2012 Ron receptor tyrosine kinase signaling as a therapeutic target. Expert opinion on therapeutic targets 31 22834780
2019 MST1R kinase accelerates pancreatic cancer progression via effects on both epithelial cells and macrophages. Oncogene 30 30967626
2018 Inhibition of RON kinase potentiates anti-CTLA-4 immunotherapy to shrink breast tumors and prevent metastatic outgrowth. Oncoimmunology 30 30228950
2015 Juvenile skeletogenesis in anciently diverged sea urchin clades. Developmental biology 30 25641694
1998 Characterization of the mouse Ron/Stk receptor tyrosine kinase gene. Oncogene 30 9467940
2014 Hypoxia promotes nuclear translocation and transcriptional function in the oncogenic tyrosine kinase RON. Cancer research 28 24903148
2014 Regulation of Macrophage Polarization by RON Receptor Tyrosine Kinase Signaling. Frontiers in immunology 28 25400637
2022 The MST1R/RON Tyrosine Kinase in Cancer: Oncogenic Functions and Therapeutic Strategies. Cancers 27 35454943
1993 Antitumor and antimicrobial glycoproteins from sea hares. Comparative biochemistry and physiology. C, Comparative pharmacology and toxicology 27 8103724
2008 Two-stage candidate gene study of chromosome 3p demonstrates an association between nonsynonymous variants in the MST1R gene and Crohn's disease. Inflammatory bowel diseases 26 18200509
2001 Cross-talk between RON receptor tyrosine kinase and other transmembrane receptors. Histology and histopathology 26 11332718
2020 Coronaviruses in the Sea. Frontiers in microbiology 25 32793180
2017 RON and c-Met facilitate metastasis through the ERK signaling pathway in prostate cancer cells. Oncology reports 25 28440432
2016 Characterization of RON protein isoforms in pancreatic cancer: implications for biology and therapeutics. Oncotarget 25 27323855
2011 Met interacts with EGFR and Ron in canine osteosarcoma. Veterinary and comparative oncology 25 22235915
2009 Terpenyl-purines from the sea. Marine drugs 25 20098613
2020 RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer. British journal of cancer 24 33257837
2018 RON Receptor Tyrosine Kinase as a Therapeutic Target for Eradication of Triple-Negative Breast Cancer: Efficacy of Anti-RON ADC Zt/g4-MMAE. Molecular cancer therapeutics 24 30275241
2013 Pathogenesis of RON receptor tyrosine kinase in cancer cells: activation mechanism, functional crosstalk, and signaling addiction. Journal of biomedical research 24 24086167
2011 Requirement for LMP1-induced RON receptor tyrosine kinase in Epstein-Barr virus-mediated B-cell proliferation. Blood 24 21659546
2014 The RON receptor tyrosine kinase in pancreatic cancer pathogenesis and its potential implications for future targeted therapies. Pancreas 23 24518495
2017 RON Signaling Is a Key Mediator of Tumor Progression in Many Human Cancers. Cold Spring Harbor symposia on quantitative biology 22 28057847
2011 Laboratory on sea urchin fertilization. Molecular reproduction and development 22 21805525
2013 Ron knockdown and Ron monoclonal antibody IMC-RON8 sensitize pancreatic cancer to histone deacetylase inhibitors (HDACi). PloS one 21 23922886
2010 The RON tyrosine kinase receptor regulates vascular endothelial growth factor production in pancreatic cancer cells. Pancreas 21 20358644
2009 The Ron receptor tyrosine kinase negatively regulates mammary gland branching morphogenesis. Developmental biology 21 19576199
2008 The receptor tyrosine kinase RON represses HIV-1 transcription by targeting RNA polymerase II processivity. Journal of immunology (Baltimore, Md. : 1950) 21 18209063
2005 Ron tyrosine kinase receptor regulates papilloma growth and malignant conversion in a murine model of skin carcinogenesis. Oncogene 21 15531916
2007 Human RON receptor tyrosine kinase induces complete epithelial-to-mesenchymal transition but causes cellular senescence. Biochemical and biophysical research communications 20 17588532
2002 Activation of the RON receptor tyrosine kinase protects murine macrophages from apoptotic death induced by bacterial lipopolysaccharide. Journal of leukocyte biology 19 11818458
1998 Characterization of two monoclonal antibodies against the RON tyrosine kinase receptor. Hybridoma 19 9890710
2019 Gastrulation in the sea urchin. Current topics in developmental biology 18 31959288

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