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MST1R (Macrophage stimulating 1 receptor)

Identity

Other namesC-MET-related tyrosine kinase (RON)
RON protein tyrosine kinase (RON);
Macrophage stimulating protein receptor (MSP-receptor)
HGNC (Hugo) MST1R
LocusID (NCBI) 4486
Location 3p21.31
Location_base_pair Starts at 49924436 and ends at 49941306 bp from pter ( according to hg19-Feb_2009)  [Mapping]
Local_order between LIMD1 and CCXCR1; between D3S1568 and D3S3822

DNA/RNA

 
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

Protein

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 The SEMA domain (consisting of most of a- and part of b- chain) contains the ligand (MSP) binding pocket (unpublished data).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

External links

Nomenclature
HGNC (Hugo)MST1R   7381
Cards
AtlasRONID287
Entrez_Gene (NCBI)MST1R  4486  macrophage stimulating 1 receptor (c-met-related tyrosine kinase)
GeneCards (Weizmann)MST1R
Ensembl (Hinxton)ENSG00000164078 [Gene_View]  chr3:49924436-49941306 [Contig_View]  MST1R [Vega]
ICGC DataPortalENSG00000164078
cBioPortalMST1R
AceView (NCBI)MST1R
Genatlas (Paris)MST1R
WikiGenes4486
SOURCE (Princeton)NM_001244937 NM_002447
Genomic and cartography
GoldenPath (UCSC)MST1R  -  3p21.31   chr3:49924436-49941306 -  3p21   [Description]    (hg19-Feb_2009)
EnsemblMST1R - 3p21 [CytoView]
Mapping of homologs : NCBIMST1R [Mapview]
OMIM600168   
Gene and transcription
Genbank (Entrez)AK303234 BP288515 BU542597 CA503122 EU826582
RefSeq transcript (Entrez)NM_001244937 NM_002447
RefSeq genomic (Entrez)AC_000135 NC_000003 NC_018914 NG_030322 NT_022517 NW_001838877 NW_004929309
Consensus coding sequences : CCDS (NCBI)MST1R
Cluster EST : UnigeneHs.517973 [ NCBI ]
CGAP (NCI)Hs.517973
Alternative Splicing : Fast-db (Paris)GSHG0021730
Alternative Splicing GalleryENSG00000164078
Gene ExpressionMST1R [ NCBI-GEO ]     MST1R [ SEEK ]   MST1R [ MEM ]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ04912 (Uniprot)
NextProtQ04912  [Medical]
With graphics : InterProQ04912
Splice isoforms : SwissVarQ04912 (Swissvar)
Catalytic activity : Enzyme2.7.10.1 [ Enzyme-Expasy ]   2.7.10.12.7.10.1 [ IntEnz-EBI ]   2.7.10.1 [ BRENDA ]   2.7.10.1 [ KEGG ]   
Domaine pattern : Prosite (Expaxy)PROTEIN_KINASE_ATP (PS00107)    PROTEIN_KINASE_DOM (PS50011)    PROTEIN_KINASE_TYR (PS00109)    SEMA (PS51004)   
Domains : Interpro (EBI)Ig-like_fold [organisation]   Ig_E-set [organisation]   IPT [organisation]   Kinase-like_dom [organisation]   Plexin-like_fold [organisation]   Prot_kinase_dom [organisation]   Protein_kinase_ATP_BS [organisation]   Semap_dom [organisation]   Ser-Thr/Tyr_kinase_cat_dom [organisation]   Tyr_kinase_AS [organisation]   Tyr_kinase_cat_dom [organisation]   Tyr_kinase_HGF/MSP_rcpt [organisation]   WD40/YVTN_repeat-like_dom [organisation]  
Related proteins : CluSTrQ04912
Domain families : Pfam (Sanger)Pkinase_Tyr (PF07714)    Sema (PF01403)    TIG (PF01833)   
Domain families : Pfam (NCBI)pfam07714    pfam01403    pfam01833   
Domain families : Smart (EMBL)IPT (SM00429)  PSI (SM00423)  Sema (SM00630)  TyrKc (SM00219)  
DMDM Disease mutations4486
Blocks (Seattle)Q04912
PDB (SRS)3PLS    4FWW   
PDB (PDBSum)3PLS    4FWW   
PDB (IMB)3PLS    4FWW   
PDB (RSDB)3PLS    4FWW   
Human Protein AtlasENSG00000164078 [gene] [tissue] [antibody] [cell] [cancer]
Peptide AtlasQ04912
HPRD02545
IPIIPI00030273   IPI00219706   IPI00956299   IPI00910383   IPI00956695   IPI00925828   IPI00925431   IPI00926020   
Protein Interaction databases
DIP (DOE-UCLA)Q04912
IntAct (EBI)Q04912
FunCoupENSG00000164078
BioGRIDMST1R
InParanoidQ04912
Interologous Interaction database Q04912
IntegromeDBMST1R
STRING (EMBL)MST1R
Ontologies - Pathways
Ontology : AmiGOstress fiber  macrophage colony-stimulating factor receptor activity  protein binding  ATP binding  integral component of plasma membrane  cellular component movement  defense response  signal transduction  transmembrane receptor protein tyrosine kinase signaling pathway  multicellular organismal development  single fertilization  positive regulation of cell proliferation  response to virus  peptidyl-tyrosine phosphorylation  enzyme binding  macrophage colony-stimulating factor signaling pathway  positive regulation of MAP kinase activity  innate immune response  positive regulation of protein kinase B signaling  
Ontology : EGO-EBIstress fiber  macrophage colony-stimulating factor receptor activity  protein binding  ATP binding  integral component of plasma membrane  cellular component movement  defense response  signal transduction  transmembrane receptor protein tyrosine kinase signaling pathway  multicellular organismal development  single fertilization  positive regulation of cell proliferation  response to virus  peptidyl-tyrosine phosphorylation  enzyme binding  macrophage colony-stimulating factor signaling pathway  positive regulation of MAP kinase activity  innate immune response  positive regulation of protein kinase B signaling  
Pathways : BIOCARTAMsp/Ron Receptor Signaling Pathway [Genes]   
Protein Interaction DatabaseMST1R
Wikipedia pathwaysMST1R
Gene fusion - rearrangments
Polymorphisms : SNP, mutations, diseases
SNP Single Nucleotide Polymorphism (NCBI)MST1R
snp3D : Map Gene to Disease4486
SNP (GeneSNP Utah)MST1R
SNP : HGBaseMST1R
Genetic variants : HAPMAPMST1R
Exome VariantMST1R
1000_GenomesMST1R 
ICGC programENSG00000164078 
Somatic Mutations in Cancer : COSMICMST1R 
CONAN: Copy Number AnalysisMST1R 
Mutations and Diseases : HGMDMST1R
Mutations and Diseases : intOGenMST1R
Genomic VariantsMST1R  MST1R [DGVbeta]
dbVarMST1R
ClinVarMST1R
Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
Diseases
OMIM600168   
MedgenMST1R
GENETestsMST1R
Disease Genetic AssociationMST1R
Huge Navigator MST1R [HugePedia]  MST1R [HugeCancerGEM]
General knowledge
Homologs : HomoloGeneMST1R
Homology/Alignments : Family Browser (UCSC)MST1R
Phylogenetic Trees/Animal Genes : TreeFamMST1R
Chemical/Protein Interactions : CTD4486
Chemical/Pharm GKB GenePA31186
Clinical trialMST1R
Cancer Resource (Charite)ENSG00000164078
Other databases
Probes
Litterature
PubMed108 Pubmed reference(s) in Entrez
CoreMineMST1R
iHOPMST1R
OncoSearchMST1R

Bibliography

A serum protein that stimulates macrophage movement, chemotaxis and spreading.
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PMID 976357
 
The v-sea oncogene of avian erythroblastosis retrovirus S13: another member of the protein-tyrosine kinase gene family.
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RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP.
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A mutation in the RET proto-oncogene associated with multiple endocrine neoplasia type 2B and sporadic medullary thyroid carcinoma.
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Molecular cloning of a novel receptor tyrosine kinase gene, STK, derived from enriched hematopoietic stem cells.
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PMID 8193352
 
Action and target cell specificity of human macrophage-stimulating protein (MSP).
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PMID 8157975
 
Identification of the ron gene product as the receptor for the human macrophage stimulating protein.
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PMID 7939629
 
The proto-oncogene RON is involved in development of epithelial, bone and neuro-endocrine tissues.
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PMID 8545120
 
Terminal differentiation of murine resident peritoneal macrophages is characterized by expression of the STK protein tyrosine kinase, a receptor for macrophage-stimulating protein.
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PMID 7579443
 
Modulation of megakaryocytopoiesis by human macrophage-stimulating protein, the ligand for the RON receptor.
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PMID 8609414
 
A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype.
Collesi C, Santoro MM, Gaudino G, Comoglio PM
Molecular and cellular biology. 1996 ; 16 (10) : 5518-5526.
PMID 8816464
 
Macrophage-stimulating protein activates STK receptor tyrosine kinase on osteoclasts and facilitates bone resorption by osteoclast-like cells.
Kurihara N, Iwama A, Tatsumi J, Ikeda K, Suda T
Blood. 1996 ; 87 (9) : 3704-3710.
PMID 8611695
 
The tyrosine kinase receptors Ron and Sea control scattering and morphogenesis of liver progenitor cells in vitro.
Medico E, Mongiovi AM, Huff J, Jelinek MA, Follenzi A, Gaudino G, Parsons JT, Comoglio PM
Molecular biology of the cell. 1996 ; 7 (4) : 495-504.
PMID 8730094
 
Cloning and expression of Xenopus HGF-like protein (HLP) and Ron/HLP receptor implicate their involvement in early neural development.
Nakamura T, Aoki S, Takahashi T, Matsumoto K, Kiyohara T, Nakamura T
Biochemical and biophysical research communications. 1996 ; 224 (2) : 564-573.
PMID 8702427
 
Role of c-kit receptor tyrosine kinase in the development, survival and neoplastic transformation of mast cells.
Tsujimura T
Pathology international. 1996 ; 46 (12) : 933-938.
PMID 9110344
 
Macrophage-stimulating protein induces proliferation and migration of murine keratinocytes.
Wang MH, Dlugosz AA, Sun Y, Suda T, Skeel A, Leonard EJ
Experimental cell research. 1996 ; 226 (1) : 39-46.
PMID 8660937
 
Requirement of phosphatidylinositol-3 kinase for epithelial cell migration activated by human macrophage stimulating protein.
Wang MH, Montero-Julian FA, Dauny I, Leonard EJ
Oncogene. 1996 ; 13 (10) : 2167-2175.
PMID 8950984
 
Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas.
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Overexpression of the RON gene in human breast carcinoma.
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PMID 9671413
 
Point mutations in the tyrosine kinase domain release the oncogenic and metastatic potential of the Ron receptor.
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PMID 9715276
 
Characterization of the mouse Ron/Stk receptor tyrosine kinase gene.
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Macrophage-stimulating protein and its receptor in non-small-cell lung tumors: induction of receptor tyrosine phosphorylation and cell migration.
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PMID 9533936
 
Domains in plexins: links to integrins and transcription factors.
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PMID 10390613
 
Macrophage stimulating protein-induced epithelial cell adhesion is mediated by a PI3-K-dependent, but FAK-independent mechanism.
Danilkovitch A, Skeel A, Leonard EJ
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PMID 10222149
 
The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse.
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PMID 10225971
 
Presence of RON receptor tyrosine kinase and its splicing variant in malignant and non-malignant human colonic mucosa.
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PMID 10493952
 
Fv2 encodes a truncated form of the Stk receptor tyrosine kinase.
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PMID 10508511
 
Chicken macrophage stimulating protein is a ligand of the receptor protein-tyrosine kinase Sea.
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PMID 10473593
 
Gene structure of the human receptor tyrosine kinase RON and mutation analysis in lung cancer samples.
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PMID 10959094
 
Overexpression and activation of the RON receptor tyrosine kinase in a panel of human colorectal carcinoma cell lines.
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PMID 11082293
 
Two independent signaling pathways mediate the antiapoptotic action of macrophage-stimulating protein on epithelial cells.
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PMID 10688668
 
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Contributor(s)

Written01-2001Debora Angeloni, Michael I. Lerman
Laboratory of Immunobiology, National Cancer Institute, Frederick Cancer Research Facility Bldg. 560 Rm. 12 26 Frederick, MD 21702, USA

Citation

This paper should be referenced as such :
Angeloni, D ; Lerman, MI
MST1R (macrophage stimulating 1 receptor)
Atlas Genet Cytogenet Oncol Haematol. 2001;5(1):23-26.
Free online version   Free pdf version   [Bibliographic record ]
URL : http://AtlasGeneticsOncology.org/Genes/RONID287.html

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indexed on : Tue Sep 23 19:26:37 CEST 2014

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