Oncogene database

4486

MST1R

macrophage stimulating 1 receptor;MST1R;macrophage stimulating 1 receptor

MSP receptor|MST1R variant RON30|MST1R variant RON62|PTK8 protein tyrosine kinase 8|RON variant 21|RON variant E2E3|c-met-related tyrosine kinase|macrophage stimulating 1 receptor (c-met-related tyrosine kinase)|macrophage-stimulating protein receptor|p18

3p21.3

protein-coding

RON, a member of the MET proto-oncogene family, has been implicated in the progression of certain epithelial cancers. The purpose of this study was to determine the oncogenic potential of RON in vivo in lung epithelial cells. Transgenic mice were established using surfactant protein C promoter to express human RON in the distal lung epithelial cells. These mice were born normal but developed multiple lung tumors with distinct morphology and growth patterns. tumors appeared as a single mass in the lung around 2 months of age and gradually developed into multiple nodules located mostly in the peripheral portions of the lung. A transition from early adenomas to later adenocarcinomas was observed. Morphologically, tumors were characterized as cuboidal epithelial cells with a type II cell phenotype, grew along the alveolar walls, and projected into the alveolar septa. RON was highly expressed and constitutively activated in tumors. These results indicate that overexpression of human wild-type RON causes the formation of lung tumors with unique biological characteristics in vivo. This model provides opportunities to study the role of RON in the pathogenesis of lung tumors and to elucidate the mechanisms underlying this distinct lung tumor.

The proto-oncogene product Ron is the receptor for macrophage stimulating protein, a scatter factor that stimulates cell proliferation, prevents apoptosis, and induces an invasive cell phenotype. We investigated the expression of Ron, Ki-67 (proliferation index), p53, and bcl-2 (proapoptotic and antiapoptotic proteins, respectively) in 50 renal tumors (19 clear cell carcinomas, 18 oncocytomas, 7 papillary cell carcinomas, 5 chromophobe cell carcinomas, and 1 carcinoma with sarcomatoid areas). In addition, we studied Ron in normal kidney and in the renal carcinoma cell line Caki-1. Immunostaining and Western blot showed Ron in normal kidney and in ALL oncocytomas but never in renal cell carcinomas or in Caki-1. In addition, Western blot showed that Ron was expressed in phosphorylated, i.e., active, form. Bcl-2 was strongly expressed in oncocytomas, whereas Ki-67 and p53 were much less expressed in oncocytomas than in carcinomas. These results indicate in Ron a marker that differentiates oncocytoma from the other renal epithelial tumors. We therefore think that Ron may prove to be a new tool for a sound and precise diagnosis of oncocytoma, a benign tumor that cannot always be distinguished from carcinomas at histologic examination. The overexpression of bcl-2, but not p53 in oncocytoma, suggests that the MSP/Ron system sustains the growth of oncocytoma by opposing apoptosis.

Recently, it was reported that RON proto-oncogene, encoding a receptor tyrosine kinase, was strongly expressed in renal oncocytomas but not in any renal cell carcinomas, including 5 chromophobe renal cell carcinomas, which morphologically resemble oncocytomas. To determine its diagnostic value, we studied Ron protein expression by immunohistochemistry in a larger number of renal cell neoplasms with emphasis on chromophobe renal cell carcinomas. Tissue microarrays containing 141 renal cell neoplasms, including 55 oncocytomas and 52 chromophobe renal cell carcinomas, were constructed. In addition, conventional sections from 15 cases of oncocytoma and 5 cases of chromophobe renal cell carcinoma were analyzed. Immunohistochemistry was carried out with a monoclonal mouse anti-human Ron-alpha antibody. Staining intensity was scored on a 0 to 3 scale. Ninety-nine percent of oncocytomas (69 of 70) and 96% of chromophobe renal cell carcinomas (55 of 57) showed moderate to strong, diffuse cytoplasmic Ron immunoreactivity with intensities > or =2, while only 17% of other renal cell carcinoma subtypes stained with intensities > or =2. Our study indicates that Ron immunostaining cannot be used to distinguish oncocytoma from chromophobe renal cell carcinoma.

RON (recepteur d origine nantais), a tyrosine kinase receptor for macrophage-stimulating protein (MSP) was implicated in tumor progression. However, it was not investigated how this important oncogene is regulated. We show that MSP promotes invasion of MDA MB 231 and MDA MB 468 but not MCF-7 breast cancer cells. Reverse transcription-PCR and Western analysis indicated the expression of RON message and protein, respectively, in MDA MB 231 and MDA MB 468 cells but not in MCF-7 cells. RON expression correlated with Sp1 expression. Initial analysis of a 1.2-kb and 400-bp RON promoter in MDA MB 231 and MDA MB 468 cells suggested the presence of ALL the necessary regulatory elements within 400 bp from the transcription start site. Site-directed mutagenesis of the 400-bp RON promoter revealed that the overlapping Sp1 sites at-94 (Sp1-3/4) and Sp1 site at -113 (Sp1-5) are essential for RON gene transcription. Electrophoretic mobility shift assays and chromatin immunoprecipitation analysis indicated that Sp1 binding to these sites is required for RON promoter activity. Ectopic Sp1 expression in Sp1 null SL2 cells confirmed the involvement of these Sp1 sites in the regulation of oncogenic RON tyrosine kinase. Treatment of MDA MB 231 cells with mithramycin A, an inhibitor of Sp1 binding, or siRNA knock-down of Sp1 blocked RON gene expression and MSP-mediated invasion of MDA MB 231 cells. This is the first report demonstrating a clear link between Sp1-dependent RON tyrosine kinase expression and invasion of breast carcinoma cells.

Alternative splicing is a key molecular mechanism for increasing the complexity of the human transcriptome. Nearly ALL human genes are regulated by alternative splicing and the deregulation of this process has a causative role in various human diseases, including cancer. The discovery that alternatively spliced isoforms of several genes are expressed selectively in tumor cells opened the exciting possibility that pharmacological treatment of aberrant splicing could lead to new anti-cancer therapeutic approaches. An alternatively spliced isoform of a scatter factor receptor and proto-oncogene, Ron, accumulates during tumor progression of epithelial tissues and is able to confer an invasive phenotype to the expressing cells. This isoform, called DeltaRon, originates from skipping of exon 11, and this specific splicing event is controlled by the expression level of the splicing factor and proto-oncogene SF2/ASF. Over-expression of SF2/ASF, which occurs frequently in various human tumors, induces the production of DeltaRon and activates the epithelial to mesenchymal transition (EMT), leading to increased cell motility. In this paper, we have used targeted oligonucleotide enhancers of splicing (TOES) to recruit positive splicing factors to Ron exon 11 and thereby stimulate its inclusion. As an alternative approach, we have used selected indole derivatives that target ASF/SF2 splicing activity. Both treatments correct aberrant DeltaRon splicing, restoring the incorporation of Ron exon 11. Notably, indole derivatives are also able to affect the invasive phenotype of the cells. Thus, these treatments may have therapeutic applications for anti-cancer purposes.

AIM: To evaluate the effects of HSP90 blockade by EC154 on the oncogenic receptor tyrosine kinase macrophage-stimulating 1 receptor (MST1R) in gastric and pancreatic cancer. MATERIALS AND METHODS: Impact of EC154 on signaling pathways was investigated by western blotting. cancer cell migration was evaluated in Boyden chambers. Transcriptional regulation of MST1R was examined by using promoter-luciferase reporter constructs. Effects on MST1R expression, and tumor growth were investigated in in vivo tumor models. RESULTS: MST1R was expressed by cancer cells without evidence of MST1R mutations. EC154 led to an effective inhibition of cancer cell growth, down-regulated MST1R, diminished its promoter activity, and disrupted oncogenic macrophage-stimulating protein 1 (MSP1) signaling. Moreover, pro-migratory activities of cancer cells were dramatically inhibited. In vivo, treatment with EC154 significantly reduced tumor growth, while MST1R expression was down-regulated. CONCLUSION: Wild-type MST1R is an HSP90 client protein that can be targeted in gastrointestinal cancer using HSP90 inhibitors.

RON is a proto-oncogene that induces cell dissociation, migration and matrix invasion. RON160, a splicing variant of RON, is a natural splicing product in colon cancers that is produced through skipping of exons 5 and 6 in alternative splicing process. RON160 promotes cellular transformation in vitro and tumor formation in vivo. We present, here, two novel splicing variants of RON in the partial splicing events that involve exons 5 and 6. The common facts of these two novel splicing variants are that exons 4-7 are included. In addition, intron 4 is spliced whereas intron 5 is included in both variants. The difference of these two isoforms is the inclusion or skipping of intron 6. In one variant intron 6 is included, but intron 6 is skipped in another variant. These two variants should be truncated but these proteins have not yet been detected.

Ron is a human receptor for the macrophage-stimulating protein (MSP). Exon 11 skipping of Ron pre-mRNA produces the Ron165 protein that has a deletion of a 49 amino acid region in the beta-chain extracellular domain. Ron165 is constitutively active even in the absence of its ligand. Through stepwise deletion analysis, we identified a 2-nt RNA enhancer, which is located 74 nt upstream from the 5 splice site of exon 11, for exon 11 inclusion. Through double-base and single-base substitution analysis of the 2-nt RNA, we demonstrated that the GA, CC, UG and AC dinucleotides on exon 11, in addition to the wild-type AG sequence, function as enhancers for exon 11 inclusion of the Ron pre-mRNA.

tumor hypoxia drives metastatic progression, drug resistance, and posttreatment relapses, but how cancer cells adapt and evolve in response to hypoxic stress is not well understood. In this study, we address this question with the discovery that the receptor tyrosine kinase RON translocates into the nucleus of hypoxic cancer cells. In response to hypoxia, nuclear RON interacts with the hypoxia-inducible factor HIF-1alpha in a manner that relies on RON tyrosine kinase activity, binding to the c-JUN promoter and activating it. Mechanistic investigations revealed unexpectedly that nuclear RON played a more important role in activation of the c-JUN promoter than HIF-1alpha, leading to increased cell proliferation, survival adaptation, in vitro migration, and tumorigenicity under hypoxic conditions. Taken together, our results pointed to a novel function for RON as a transcriptional regulator that promotes the survival of cancer cells subjected to hypoxia. These results suggest novel implications for the use of small-molecule inhibitors or monoclonal antibodies targeting the RON kinase in the prevention or treatment of advanced cancer.

We previously showed that the proto-oncogene RON encodes the tyrosine kinase receptor for Macrophage Stimulating Protein (MSP), originally isolated as a chemotactic factor for peritoneal macrophages. To elucidate the biological role of MSP we studied the expression of the Ron receptor in vivo, and the response to the factor in vitro. RON specific transcripts were detectable in mouse liver from early embryonal life (day 12.5 p.c.) through adult life. Adrenal gland, spinal ganglia, skin, lung and--unexpectedly--ossification centers of developing mandible, clavicle and ribs were also positive at later stages (day 13.5-16.5 p.c.). From day 17.5 RON was expressed in the gut epithelium and in a specific area of the central nervous system, corresponding to the nucleus of the hypoglossus. In adult mouse tissues RON transcripts were observed in brain, adrenal glands, gastro-intestinal tract, testis and kidney. Epithelial, osteoclast-like and neuroendocrine cells express the Ron receptor and respond to MSP in vitro. In the neuroendocrine PC12 cell line, while NGF induced growth arrest and morphological differentiation, MSP behaved as a strong mitogen. These findings show that the Ron receptor and its ligand are involved in the development of epithelial tissues, bones, and neuroendocrine derivatives driving cells towards the proliferation program.