Met Knockin mouse models

Receptor tyrosine kinase MET, encoded in mouse by Met, is the single-pass receptor for hepatocyte growth factor, comprising a SEMA domain, PSI and IPT repeats, and a cytoplasmic kinase domain whose phosphorylated Y1349 and Y1356 residues recruit GAB1 and GRB2 to activate RAS-ERK, PI3K-AKT, and STAT3, driving epithelial morphogenesis, hepatocyte survival, and myoblast migration. Oncogenic activation occurs through amplification, exon 14 skipping that removes the CBL-binding juxtamembrane degron and stabilizes the receptor, kinase domain germline mutations such as M1250T in hereditary papillary renal carcinoma, and TPR-MET rearrangement. Germline nulls die near midgestation from placental and hepatic failure, so conditional deletion is required for regeneration and tumor dependency studies, while exon 14 skipping or kinase domain knockins model ligand-independent signaling and inhibitor response. Since HGF binding is species selective, humanized MET or ligand-humanized alleles are essential for antibody and antibody-drug conjugate testing; pair these with epithelial Cre lines matched to the intended tumor lineage.

Knockin designs at Met support head to head comparisons between wild type and modified alleles because regulatory DNA stays in place.