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

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 The SEMA domain (consisting of most of a- and part of b- chain) contains the ligand (MSP) binding pocket (unpublished data).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following normal human tissues: skin, lung, bone marrow, small intestin, heart, pancreas, thyroid, prostate, testis (unpublished data), colonic mucosa and in a variety of cell types: granulocytes and monocytes, hematopoietic cells such as erythroid and myeloid progenitor cells,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).