Alternative titles; symbols
HGNC Approved Gene Symbol: MST1R
Cytogenetic location: 3p21.31 Genomic coordinates (GRCh38) : 3:49,887,002-49,903,873 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p21.31 | {Nasopharyngeal carcinoma, susceptibility to, 3} | 617075 | Autosomal dominant | 3 |
Ronsin et al. (1993) cloned a member of the MET receptor family, which they designated RON, from a human foreskin keratinocyte cDNA library. Comparison with MET (164860), the hepatocyte growth factor receptor, suggested that the RON gene product is also a membrane-spanning disulfide-linked heterodimer with intracellular tyrosine kinase activity.
Gaudino et al. (1994) showed that the RON gene is expressed at the cell surface of several epithelial cell types in addition to granulocytes and monocytes. They found that The RON mRNA is translated into a glycosylated precursor that is cleaved into a 185-kD heterodimer of 35-kD (alpha) and 150-kD (beta) subunits joined by the predicted disulfide linkage.
Collesi et al. (1996) identified delta-RON, a RON splice variant that encodes a 165-kD protein lacking 49 amino acids in the beta subunit extracellular domain due to skipping of exon 11. Using RT-PCR, Ghigna et al. (2005) found that delta-RON was highly expressed in several human cancers, but was a minor transcript in normal human tissues.
Dai et al. (2016) found weak expression of the MST1R gene within ciliated epithelial cells of normal nasopharyngeal mucosa.
Gaudino et al. (1994) demonstrated that the RON beta chain undergoes tyrosine phosphorylation upon stimulation by macrophage-stimulating protein (MSP; 142408), a protein structurally related to hepatocyte growth factor (HGF; 142409).
Experiments by Wang et al. (1994) established that the RON gene product is a specific cell surface receptor for MSP.
Sakamoto et al. (1997) showed that the RON tyrosine kinase, the receptor for MSP, is expressed on the ciliated epithelia of the mucociliary transport apparatus of the lung. Furthermore, they showed that MSP stimulated ciliary motility in these cells by activating RON. Sakamoto et al. (1997) suggested that the MSP-RON signaling pathway is a novel regulatory system of mucociliary function and may be involved in host defense and fertilization.
Many tyrosine kinase receptors have been shown to be protooncogenes. Santoro et al. (1996) generated a chimeric gene, fusing RON with the promoter of the tumor potentiating region (TPR; 189940) gene. The TPR-RON fusion, transfected into fibroblasts, expressed a constitutively active form of the RON tyrosine kinase which did not transform the cells. However, Santoro et al. (1996) observed that TPR-RON did induce scatter and invasion of basement membranes in transfected cells. They concluded that RON does not behave as a conventional protooncogene but may be involved in oncogenic invasion and motility.
Collesi et al. (1996) found that delta-RON, but not full-length RON, was constitutively active in inducing cell dissociation, mobility, and invasion of extracellular matrices (i.e., cell scattering).
Ghigna et al. (2005) identified an exonic splicing silencer and an exonic splicing enhancer in exon 12 of the RON gene that regulate the inclusion or skipping of exon 11, and thus the production of delta-RON transcripts. The enhancer element contains a consensus binding motif for SF2 (SFRS1; 600812), and Ghigna et al. (2005) demonstrated that SF2 binds the enhancer element and regulates splicing of endogenous RON. Collesi et al. (1996) had shown that overexpression of delta-RON resulted in loss of epithelial phenotype, with acquisition of spindle-shaped morphology, increased cell motility, and aggressive behavior. Ghigna et al. (2005) found that overexpression of SF2 elicited similar effects. Downregulation of SF2 by small interfering RNA reduced the level of delta-RON, which in turn decreased cell motility. Ghigna et al. (2005) concluded that SF2 controls cell scattering by regulating splicing of RON.
By overexpressing RON in monocytes/macrophages, Lee et al. (2004) found that RON inhibited human immunodeficiency virus (HIV)-1 proviral transcription by decreasing the binding activity of NFKB (see 164011) to the HIV-1 long terminal repeat. RT-PCR, immunoblot, and immunohistochemical analyses revealed RON expression in fetal brain, primary astrocytes, and monocyte-derived cells in brain. RON expression was detected in all control adult brains examined, but expression of RON was reduced in 6 of 9 patients with acquired immunodeficiency syndrome (AIDS), including all 3 AIDS patients with encephalitis. Lee et al. (2004) proposed that HIV-1 may directly or indirectly target RON to disrupt normal signals that actively suppress inflammation to assure a microenvironment favorable for virus replication.
By isotopic in situ hybridization, Ronsin et al. (1993) mapped the RON gene to chromosome 3p21, with the most probable location being 3p21.3. The gene encoding MSP is also located on 3p21, a region of frequent deletion or mutation in small cell lung and renal carcinoma.
By whole-exome sequencing of 161 cases of nasopharyngeal carcinoma (see NPCA3, 617075) and 895 controls from southern China, Dai et al. (2016) found a significant association between variation in the MST1R gene and development of the cancer. The variants, which were confirmed by Sanger sequencing, were filtered against the 1000 Genomes Project and Exome Sequencing Project databases. Eleven variants, including 1 frameshift and 10 missense variants located at conserved residues, were found in 13 patients (8.7%), including 2 sibs. Seven of the 13 patients had early onset, before 20 years of age: 5 heterozygous missense variants were observed in 17.9% of the early-onset cases and in only 1.2% of controls (p = 7.94 x 10(-12)). The variants identified in the early-onset cases were A973T, E705K, V670G, A327T, and R306H (600168.0001). Functional studies of the variants were not performed. However, copy number alterations of 3p21.2 (loss of heterozygosity) were found in 9 (64%) of 14 tumors derived from individuals with germline MST1R variants. In addition, proximal promoter hypermethylation resulting in downregulation of full-length MST1R was also frequently observed. Overall, the findings suggested that variation in expression of the MST1R gene, including germline variation, may predispose to the development of nasopharyngeal carcinoma. No somatic MST1R mutations were found in over 100 NPC tumors.
RON activation results in a variety of cellular responses in vitro, such as activation of macrophages, proliferation, migration, and invasion, suggesting a broad biologic role in vivo. Nevertheless, Msp-deficient mice grow to adulthood with few appreciable phenotypic abnormalities. Muraoka et al. (1999) found that in striking contrast to the loss of its only known ligand, complete loss of Ron led to early embryonic death. Embryos that were devoid of Ron were viable through the blastocyst stage of development but failed to survive past the periimplantation period. In situ hybridization analysis demonstrated that Ron is expressed in the trophectoderm at embryonic day 3.5 and is maintained in extraembryonic tissue through embryonic day 7.5, compatible with an essential function at this stage of development. Hemizygous mice (Ron +/-) grew to adulthood; however, these mice were highly susceptible to endotoxic shock and appeared to be compromised in their ability to downregulate nitric oxide production. These results demonstrated a novel role for Ron in early mouse development and suggested that Ron plays a limited role in the inflammatory response.
In a patient (HK_12) from southern China who developed nasopharyngeal carcinoma (NPCA3; 617075) at age 17 years, Dai et al. (2016) identified a heterozygous c.917G-A transition in exon 1 of the MST1R gene, resulting in an arg306-to-his (R306H) substitution at a conserved residue in the Sema domain, which is important for ligand binding and receptor activation. The mutation occurred at a CpG site. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, was not found in the 1000 Genomes Project and Exome Variant Server databases. It was found at a very low frequency (0.0006) among 895 controls. The patient was part of a cohort of 161 NPC patients from southern China who underwent whole-exome sequencing. Screening for this variant in a second cohort of 2,160 unrelated NPC cases and 2,433 controls found an additional 8 patients (0.4%) who carried this heterozygous variant, whereas it was only found in 1 control (odds ratio of 9.0, p = 0.0079). Functional studies of the variant were not performed.
Collesi, C., Santoro, M. M., Gaudino, G., Comoglio, P. M. A splicing variant of the RON transcript induces constitutive tyrosine kinase activity and an invasive phenotype. Molec. Cell. Biol. 16: 5518-5526, 1996. Note: Erratum: Molec. Cell. Biol. 17: 528 only, 1997. [PubMed: 8816464] [Full Text: https://doi.org/10.1128/MCB.16.10.5518]
Dai, W., Zheng, H., Cheung, A. K. L., Tang, C. S., Ko, J. M. Y., Wong, B. W. Y., Leong, M. M. L., Sham, P. C., Cheung, F., Kwong, D. L.-W., Ngan, R. K. C., Ng, W. T., and 14 others. Whole-exome sequencing identifies MST1R as a genetic susceptibility gene in nasopharyngeal carcinoma. Proc. Nat. Acad. Sci. 113: 3317-3322, 2016. [PubMed: 26951679] [Full Text: https://doi.org/10.1073/pnas.1523436113]
Gaudino, G., Follenzi, A., Naldini, L., Collesi, C., Santoro, M., Gallo, K. A., Godowski, P. J., Comoglio, P. M. RON is a heterodimeric tyrosine kinase receptor activated by the HGF homologue MSP. EMBO J. 13: 3524-3532, 1994. [PubMed: 8062829] [Full Text: https://doi.org/10.1002/j.1460-2075.1994.tb06659.x]
Ghigna, C., Giordano, S., Shen, H., Benvenuto, F., Castiglioni, F., Comoglio, P. M., Green, M. R., Riva, S., Biamonti, G. Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene. Molec. Cell 20: 881-890, 2005. [PubMed: 16364913] [Full Text: https://doi.org/10.1016/j.molcel.2005.10.026]
Lee, E. S., Kalantari, P., Tsutsui, S., Klatt, A., Holden, J., Correll, P. H., Power, C., Henderson, A. J. RON receptor tyrosine kinase, a negative regulator of inflammation, inhibits HIV-1 transcription in monocytes/macrophages and is decreased in brain tissue from patients with AIDS. J. Immun. 173: 6864-6872, 2004. [PubMed: 15557181] [Full Text: https://doi.org/10.4049/jimmunol.173.11.6864]
Muraoka, R. S., Sun, W. Y., Colbert, M. C., Waltz, S. E., Witte, D. P., Degen, J. L., Degen, S. J. F. The Ron/STK receptor tyrosine kinase is essential for peri-implantation development in the mouse. J. Clin. Invest. 103: 1277-1285, 1999. [PubMed: 10225971] [Full Text: https://doi.org/10.1172/JCI6091]
Ronsin, C., Muscatelli, F., Mattei, M.-G., Breathnach, R. A novel putative receptor protein tyrosine kinase of the met family. Oncogene 8: 1195-1202, 1993. [PubMed: 8386824]
Sakamoto, O., Iwama, A., Amitani, R., Takehara, T., Yamaguchi, N., Yamamoto, T., Masuyama, K., Yamanaka, T., Ando, M., Suda, T. Role of macrophage-stimulating protein and its receptor, RON tyrosine kinase, in ciliary motility. J. Clin. Invest. 99: 701-709, 1997. [PubMed: 9045873] [Full Text: https://doi.org/10.1172/JCI119214]
Santoro, M. M., Collesi, C., Grisendi, S., Gaudino, G., Comoglio, P. M. Constitutive activation of the RON gene promotes invasive growth but not transformation. Molec. Cell. Biol. 16: 7072-7083, 1996. Note: Erratum: Molec. Cell. Biol. 17: 1758 only, 1994. [PubMed: 8943362] [Full Text: https://doi.org/10.1128/MCB.16.12.7072]
Wang, M.-H., Ronsin, C., Gesnel, M.-C., Coupey, L., Skeel, A., Leonard, E. J., Breathnach, R. Identification of the RON gene product as the receptor for the human macrophage stimulating protein. Science 266: 117-119, 1994. [PubMed: 7939629] [Full Text: https://doi.org/10.1126/science.7939629]