| Hepatocyte growth factor beta chain is the serine protease–like subunit of the heterodimeric HGF ligand, a plasminogen‑related growth factor that binds and activates the Met receptor tyrosine kinase to regulate epithelial proliferation, motility, and morphogenesis. The mature cytokine arises from a single‑chain precursor that is cleaved by extracellular serine proteases into disulfide‑linked alpha and beta chains, where the alpha chain carries the high‑affinity Met‑binding kringle and N‑terminal domains, and the beta chain provides a protease‑like domain that resembles chymotrypsin‑family serine proteases but lacks catalytic activity and functions as an auxiliary Met‑binding and signaling module. The beta chain adopts a zymogen‑like fold with an “active‑site region” and an “activation domain” that align with the catalytic triad and activation loop of trypsin‑like proteases, and conformational rearrangements that follow cleavage of pro‑HGF optimize this region for low‑affinity Met engagement and productive cooperation with the alpha chain on the receptor surface. Binding of HGF alpha and beta chains to distinct sites on the Met extracellular region induces receptor dimerization and trans‑autophosphorylation of intracellular tyrosines, which then recruit adaptor and effector proteins that initiate Ras–MAPK signaling for proliferation, PI3K–Akt signaling for survival, and additional cascades such as STAT and Rho‑family GTPase pathways that support scattering, branching morphogenesis, and invasive growth. The beta chain contributes directly to these outcomes by reinforcing ligand–receptor contact on Met molecules already occupied by HGF variants, sustaining receptor phosphorylation and maintaining downstream signaling required for cell spreading, motility, and tubulogenesis. Structural and mutational analyses identify clustered residues in the beta‑chain active‑site‑like and activation domains as a functional Met‑binding surface, and substitutions within this patch selectively reduce receptor phosphorylation and cell migration without abolishing high‑affinity alpha‑chain binding, indicating that the beta chain modulates signaling efficacy rather than ligand capture. Through this cooperative mechanism, the HGF beta chain participates in paracrine signaling that drives liver regeneration, epithelial repair, and angiogenic remodeling, and it also supports invasive tumor growth when the HGF–Met axis is dysregulated by ligand overproduction, aberrant activation, or receptor overexpression in carcinomas. |
