Fig. 1

Schematic representation of MET and RON, their ligands HGF and MSP, and representative isoforms. (a)Both MET and RON are first synthesized as a biologically inactive single-chain precursor (pro-MET and pro-RON). Mature MET is composed of a 45 KDa α-chain and a 145 kDa β-chain linked by a disulfide bound. Similarly, mature RON consists of a 40 kDa α-chain linked through a disulfide bond to a 145 kDa β-chain. Structurally, both MET and RON consist of a large extracellular domain, a short transmembrane (TM) segment, and a cytoplasmic portion harboring a tyrosine kinase (TK) domain and a C-terminal tail. The β-chain of MET and RON contains a large portion of the semaphorin (SEMA) domain followed by a plexin-semaphorin-integrin (PSI) domain and 3 or 4 immunoglobulin-like plexin and transcription (IPT) motifs. Regulatory tyrosine residues, Tyr¹³³⁴ and Tyr¹³³⁵ in the MET TK domain and Tyr¹²³⁸ and Tyr¹²³⁹ in the RON TK domain, are indicated. Also, Tyr¹³⁴⁹ and Tyr¹³⁵⁶ in the MET C-terminal tail and Tyr¹³⁵³ and Tyr¹³⁶⁰ in the RON C-terminal tail, which form the functional docking site, respectively, are marked. (b) Both HGF and MSP are first synthesized as biologically inactive single-chain precursors known as pro-HGF and pro-MSP. Proteolytic cleavage results in a biologically active two-chain form of mature HGF and MSP. Both α-chains of HGF and MSP contains a hairpin loop (HPL) followed by four kringle domains (K1 to K4). Both β-chains of HGF and MSP contain a serine protease-like domain (SPLD) with substation of amino acids in the active site. The high affinity MET-binding site is in the HGF α-chain and the low affinity MET-binding site is in the HGF β-chain. In contrast, the major RON-binding site is in the MSP β-chain and the minor RON-binding site is in the MSP α-chain. (c) Representative MET isoforms and RON variants are presented. MET-TPR is a 65 KDa fusion protein generated by a chromosomal rearrangement between the translocated promoter region (TPR) and the MET intracellular sequence containing the kinase domain and the C-terminal tail. MET^T992I mutant is a constitutively active isoform identified in CRAC samples. MET exon-14 skipping variant is produced by aberrant splicing due to mutations leading to exon 14 skipping. This variant is unable to interact with the E3 ubiquitin-protein ligase CBL leading to impaired MET degradation with enhanced tumorigenic activity. Splicing variants of RON include RONΔ165 with a deletion of exon 11; RONΔ160 with a combined deletion of exons 5 and 6; RONΔ155 with a combined deletion of exons 5, 6, and 11; and short form (SF) RON, which is initiated by an alternative promoter in the RON gene