MST1R (Macrophage stimulating 1 receptor)

2001-01-01   Debora Angeloni , Michael I. Lerman 

Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research Facility Bldg. 560 Rm. 12 26 Frederick, MD 21702, USA




Atlas Image


Twenty coding exons. All exons are small in size, ranging from 93 bp to 253 bp, with the exception of exon 1 (>1 kb). Exon 1, 2 and 3 code for the SEMA domain of the RON protein (red). Exons 4 codes for a PSI domain (orange), a modular structure about 50 amino acid long containing eight conserved Cys residues, putatively involved in protein-protein interactions. The sequence between exon 4 and 12 codes for four repeated modular structures called IPT (yellow); these domains are found in cell surface receptors such as MET and RON as well as in intracellular transcription factors where they are involved in DNA binding. Part of exon 12 codes for the transmembrane domain, (pink). Exons 14 to 20 codes for the kinase domain (blue).Four-digit numbers refer to splice sites location, based on RON cDNA sequence


Two major transcripts are detected, respectively 4.5 kb and 2 kb. ORF: 4204 bp


Atlas Image


The RON protein is a glycosilated heterodimeric protein composed of one a- (35 kD) and one b-chain (150 kD) linked by an unknown number of disulfide bonds. The two chains derive from a single-chain precursor of about 185 kD that undergoes proteolytic cleavage at the basic amino acid site KRRRR. The a-chain is extracellular. The b-chain has an extracellular part, a one-pass transmembrane helix and an intracellular part containing the tyrosine kinase domain. The first 24 amino acids made the putative signal peptide (green). The SEMA domain (consisting of most of a- and part of b- chain) contains the ligand (MSP) binding pocket (unpublished data). Tyrosine residues 1238 and 1239 (upward arrowheads in the figure) are essential for up-regulation of RON catalytic activity. Tyrosine residues1353 and 1360 (downward arrowheads, in the figure) make a docking site that mediates high affinity interactions with multiple SH2-containing signal transducers


RON is expressed in human keratinocytes (it was initially cloned from a keratinocytes cDNA library). By Northern blot was found expressed in the following normal human tissues: skin, lung, bone marrow, small intestin, heart, pancreas, thyroid, prostate, testis (unpublished data), colonic mucosa and in a variety of cell types: granulocytes and monocytes, hematopoietic cells such as erythroid and myeloid progenitor cells, macrophages, osteoclasts, bone marrow megakaryocytes, epithelial and neuroendocrine cells


Transmembrane protein.


The ligand for RON is MSP. Originally, MSP was described as a serum factor enhancing the chemotactic response of murine peritoneal macrophage to the C5a fraction of complement, but RON/MSP complex has a much broader spectrum of activity. Ligand-stimulated RON activates the pathways regulating cell adhesion and motility, growth and survival. STK (the mouse ortholog) is essential for peri-implantation development during gestation, as STK-deficient mice (STK-/-) are viable only through the blastocyst stage. Hemizygous mice (STK+/-) grow to adulthood; however, they are highly susceptible to endotoxic shock and appear to be compromised in their ability to down-regulate nitric oxide production. These results suggest STK has a limiting role not only in the inflammatory response but also in early mouse development


RON belongs to the MET receptor tyrosine kinase (RTK) family. On the basis of the presence of multiple PSI domains and a SEMA domain, it has been proposed that plexins, MET RTK family and VESPR (virus-encoded semaphorin receptor) are classified as semaphorins. RON orthologs have been identified in mouse (STK), chicken (c-sea) and Xenopus



Several Single Nucleotide Polymorphisms (SNPs) were found in healthy CEPH individuals: A993G :Gln322Arg (index of heterozygosity: 0.28); C4024T (same-sense variant, index of heterozygosity: 0.03); A4031G: Arg1344Gly (index of heterozygosity: 0.46)


T915C: Leu296Pro was found in the tumor DNA of one single patient affected with adenocarcinoma of the lung. The mutated protein is not constitutively activated. The mutation has no causative role in the disease. Experimental introduction in the RON kinase domain of amino acid substitutions D1232V and M1254T - initially found in the oncogenes KIT, RET and MET, involved respectively in mastocytosis, Multiple Endocrine Neoplasia type 2B and renal papillary carcinoma - results in activation of oncogenic capacity and triggers a strong metastatic activity of RON. Expression of these RON mutants causes cellular accumulation of b-catenin via inhibition of its association with the axin/GSK complex and subsequent protection from proteasomal degradation (Danilkovitch-Miagkova, personal communication).

Implicated in

Entity name
RON was found over-expressed in infiltrating breast carcinomas. A constitutively activated splicing variant of RON (lacking exon 11) was found in the gastric carcinoma cell line KATO-III. This variant induces activation of cell dissociation, motility and invasion of extracellular matrices. The same variant was found in malignant colonic mucosa. Another splicing variant, lacking exons 5 and 6, was found in the human colon carcinoma cell line HT-29.Truncated STK - the mouse RON ortholog - confers susceptibility to Friend virus-induced erythroleukemia in mice, and c-sea, the avian ortholog, causes erythroblastosis in chickens.


Pubmed IDLast YearTitleAuthors
109590942000Gene structure of the human receptor tyrosine kinase RON and mutation analysis in lung cancer samples.Angeloni D et al
86094141996Modulation of megakaryocytopoiesis by human macrophage-stimulating protein, the ligand for the RON receptor.Banu N et al
103906131999Domains in plexins: links to integrins and transcription factors.Bork P et al
110822932000Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines.Chen YQ et al
88164641996A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype.Collesi C et al
106886682000Two independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells.Danilkovitch A et al
21841201990Centre d'etude du polymorphisme humain (CEPH): collaborative genetic mapping of the human genome.Dausset J et al
85451201995The proto-oncogene RON is involved in development of epithelial, bone and neuro-endocrine tissues.Gaudino G et al
80628291994RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP.Gaudino G et al
79068661994A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.Hofstra RM et al
81933521994Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells.Iwama A et al
75794431995Terminal differentiation of murine resident peritoneal macrophages is characterized by expression of the STK protein tyrosine kinase, a receptor for macrophage-stimulating protein.Iwama A et al
86116951996Macrophage-stimulating protein activates STK receptor tyrosine kinase on osteoclasts and facilitates bone resorption by osteoclast-like cells.Kurihara N et al
9763571976A serum protein that stimulates macrophage movement, chemotaxis and spreading.Leonard EJ et al
96714131998Overexpression of the RON gene in human breast carcinoma.Maggiora P et al
87300941996The tyrosine kinase receptors Ron and Sea control "scattering" and morphogenesis of liver progenitor cells in vitro.Medico E et al
102259711999The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse.Muraoka RS et al
87024271996Cloning and expression of Xenopus HGF-like protein (HLP) and Ron/HLP receptor implicate their involvement in early neural development.Nakamura T et al
104939521999Presence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa.Okino T et al
105085111999Fv2 encodes a truncated form of the Stk receptor tyrosine kinase.Persons DA et al
83868241993A novel putative receptor protein tyrosine kinase of the met family.Ronsin C et al
97152761998Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the Ron receptor.Santoro MM et al
91403971997Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.Schmidt L et al
81579751994Action and target cell specificity of human macrophage-stimulating protein (MSP).Skeel A et al
25461511989The v-sea oncogene of avian erythroblastosis retrovirus S13: another member of the protein-tyrosine kinase gene family.Smith DR et al
91103441996Role of c-kit receptor tyrosine kinase in the development, survival and neoplastic transformation of mast cells.Tsujimura T et al
104735931999Chicken macrophage stimulating protein is a ligand of the receptor protein-tyrosine kinase Sea.Wahl RC et al
94679401998Characterization of the mouse Ron/Stk receptor tyrosine kinase gene.Waltz SE et al
86609371996Macrophage-stimulating protein induces proliferation and migration of murine keratinocytes.Wang MH et al
89509841996Requirement of phosphatidylinositol-3 kinase for epithelial cell migration activated by human macrophage stimulating protein.Wang MH et al
79396291994Identification of the ron gene product as the receptor for the human macrophage stimulating protein.Wang MH et al
95339361998Macrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration.Willett CG et al

Other Information

Locus ID:

NCBI: 4486
MIM: 600168
HGNC: 7381
Ensembl: ENSG00000164078


dbSNP: 4486
ClinVar: 4486
TCGA: ENSG00000164078


Gene IDTranscript IDUniprot

Expression (GTEx)



PathwaySourceExternal ID
Signal TransductionREACTOMER-HSA-162582
Signaling by MST1REACTOMER-HSA-8852405

Protein levels (Protein atlas)

Not detected


Pubmed IDYearTitleCitations
199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
129196772003The MSP receptor regulates alpha6beta4 and alpha3beta1 integrins via 14-3-3 proteins in keratinocyte migration.73
180732072008c-Met must translocate to the nucleus to initiate calcium signals.71
186200912008Met-related receptor tyrosine kinase Ron in tumor growth and metastasis.68
174565942007The macrophage-stimulating protein pathway promotes metastasis in a mouse model for breast cancer and predicts poor prognosis in humans.64
151848882004Interplay between scatter factor receptors and B plexins controls invasive growth.60
125278882003Altered expression of the RON receptor tyrosine kinase in primary human colorectal adenocarcinomas: generation of different splicing RON variants and their oncogenic potential.59
176166622007The RON receptor tyrosine kinase mediates oncogenic phenotypes in pancreatic cancer cells and is increasingly expressed during pancreatic cancer progression.51
201036392010Silencing of RON receptor signaling promotes apoptosis and gemcitabine sensitivity in pancreatic cancers.49
157886702005Prognostic significance of co-expression of RON and MET receptors in node-negative breast cancer patients.47


Debora Angeloni ; Michael I. Lerman

MST1R (Macrophage stimulating 1 receptor)

Atlas Genet Cytogenet Oncol Haematol. 2001-01-01

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