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

Identity

HGNC
LOCATION
3p21.31
LOCUSID
ALIAS
CD136,CDw136,NPCA3,PTK8,RON,SEA
FUSION GENES

DNA/RNA

Atlas Image

Description

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

Transcription

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

Proteins

Atlas Image

Description

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 The SEMA domain (consisting of most of a- and part of b- chain) contains the ligand (MSP) binding pocket (unpublished data).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

Expression

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

Localisation

Transmembrane protein.

Function

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

Homology

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

Mutations

Germinal

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)

Somatic

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.

Article Bibliography

Pubmed IDLast YearTitleAuthors

Other Information

Locus ID:

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

Variants:

dbSNP: 4486
ClinVar: 4486
TCGA: ENSG00000164078
COSMIC: MST1R

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000164078ENST00000296474Q04912
ENSG00000164078ENST00000344206Q04912
ENSG00000164078ENST00000411578J3KQS7
ENSG00000164078ENST00000434765H7C074
ENSG00000164078ENST00000440292H7C3Z8
ENSG00000164078ENST00000612032H2E272
ENSG00000164078ENST00000613534A0A087WZQ8
ENSG00000164078ENST00000621387Q04912

Expression (GTEx)

0
5
10
15
20
25
30
35
40

Pathways

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

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
368334442023An Introduction and Overview of RON Receptor Tyrosine Kinase Signaling.1
368334442023An Introduction and Overview of RON Receptor Tyrosine Kinase Signaling.1
323999102021Short-form RON (sf-RON) enhances glucose metabolism to promote cell proliferation via activating β-catenin/SIX1 signaling pathway in gastric cancer.7
332578372021RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer.12
334102672021Recepteur d'origine nantais contributes to the development of endometriosis via promoting epithelial-mesenchymal transition of a endometrial epithelial cells.5
335083852021Tumor cell intrinsic RON signaling suppresses innate immune responses in breast cancer through inhibition of IRAK4 signaling.10
336733462021Evidence for 2-Methoxyestradiol-Mediated Inhibition of Receptor Tyrosine Kinase RON in the Management of Prostate Cancer.2
343479142021A potential signaling axis between RON kinase receptor and hypoxia-inducible factor-1 alpha in pancreatic cancer.3
348215502021EGFR transactivates RON to drive oncogenic crosstalk.3
323999102021Short-form RON (sf-RON) enhances glucose metabolism to promote cell proliferation via activating β-catenin/SIX1 signaling pathway in gastric cancer.7
332578372021RON signalling promotes therapeutic resistance in ESR1 mutant breast cancer.12
334102672021Recepteur d'origine nantais contributes to the development of endometriosis via promoting epithelial-mesenchymal transition of a endometrial epithelial cells.5
335083852021Tumor cell intrinsic RON signaling suppresses innate immune responses in breast cancer through inhibition of IRAK4 signaling.10
336733462021Evidence for 2-Methoxyestradiol-Mediated Inhibition of Receptor Tyrosine Kinase RON in the Management of Prostate Cancer.2
343479142021A potential signaling axis between RON kinase receptor and hypoxia-inducible factor-1 alpha in pancreatic cancer.3

Citation

Debora Angeloni ; Michael I. Lerman

MST1R (Macrophage stimulating 1 receptor)

Atlas Genet Cytogenet Oncol Haematol. 2001-01-01

Online version: http://atlasgeneticsoncology.org/gene/287/gene-explorer/case-report-explorer/humanGenome