Dimer Interface in Natural Variant NK1 Is Dispensable for HGF-Dependent Met Receptor Activation

Abstract

NK1, a splicing variant of hepatocyte growth factor (HGF), binds to and activates Met receptor by forming an NK1 dimer and 2:2 complex with Met. Although the structural mechanism underlying Met activation by HGF remains incompletely resolved, it has been proposed that the NK1 dimer structure participates in this activation. We investigated the NK1 dimer interface’s role in Met activation by HGF. Because N127, V140, and K144 are closely involved in the head-to-tail NK1 dimer formation, mutant NK1 proteins with replacement of these residues by alanine were prepared. In Met tyrosine phosphorylation assays, N127-NK1, V140-NK1, and K144-NK1 showed 8.3%, 23.8%, and 52.2% activity, respectively, compared with wild-type NK1. Although wild-type NK1 promoted cell migration and scattering, N127-NK1, V140-NK1, and K144-NK1 hardly or marginally promoted them, indicating loss of activity of these mutant NK1 proteins to activate Met. In contrast, mutant HGFs (N127-HGF, V140-HGF, and K144-HGF) with the same amino acid replacements as in NK1 induced Met tyrosine phosphorylation and biological responses at levels comparable to those of wild-type HGF. These results indicate that the structural basis responsible for NK1-dependent Met dimer formation and activation differs from, or is at least distinguishable from, the structural basis responsible for HGF-dependent Met activation.

A HGF Mutation in the Familial Case of Primary Lymphedema: A Report

“…This mutation is a single nucleotide substitution (chr7:81707309G>A, hg19) that introduces a premature STOP codon, causing a truncation of the protein. It is located in the SP domain of the HGF protein, which is the domain responsible for binding to the HGF receptor [18]. This is consistent with previous reports that mostly describe mutations perturbing HGF domains important for interaction with the receptor [11][12][13].…”

Photodynamic reactions using high-intensity red LED promotes gingival wound healing by ROS induction

“…It then acts as a scaffold, allowing for the transfer of phosphorylated RTKs to the cytoplasm 38 . It has been reported that stimulation with hepatocyte growth factor (HGF), a growth factor that activates Gab1, subsequently activates the ERK1/2 pathway 39 . Gab1 has been reported to be involved in intracellular signaling pathways by fibroblast growth factor (FGF) and epidermal growth factor (EGF) 40 .…”