MET and RON receptor tyrosine kinases in colorectal adenocarcinoma: molecular features as drug targets and antibody-drug conjugates for therapy

摘要

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. METT992I 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