17 - Hepatocyte growth factor/Met signaling in cancer

Summary

Introduction

Hepatocyte growth factor (HGF), also known as scatter factor (SF), was discovered on the basis of its ability to promote liver regeneration, and independently for its mitogenic activity on epithelial cells and its ability to induce cell scatter (1). HGF is secreted primarily by mesenchymal cells and drives cell motility, proliferation, survival, and morphogenesis by binding to the Met receptor tyrosine kinase (TK) present on a variety of target cell types (1–6). HGF/Met signaling is critical for normal development and adult homeostasis: deletion of either gene lethally disrupts embryogenesis (4,6) and up-regulation of HGF expression after kidney, liver, or heart injury protects against tissue damage and promotes repair and regeneration in adults (1,7–11). Under normal conditions, Met activation is tightly regulated by paracrine ligand delivery, ligand activation, and receptor internalization, dephosphorylation, and degradation (1). Despite this, HGF/Met signaling contributes to tumorigenesis, tumor angiogenesis, and metastasis in several prevalent cancers, a realization that has driven rapid growth in the development of experimental therapeutics targeting the pathway.

HGF and Met structure and function

The human HGF gene consists of 18 exons and 16 introns spanning 68 Mb on chromosome 7q21.11 (1). Five mRNA transcripts arise from alternative splicing: two encode full-length HGF forms and three encode truncated isoforms that bind Met, but differ in their biological activities (1). HGF protein is a plasminogen family member consisting of an amino-terminal heparin-binding domain (N), four kringle domains (K1–4) and a carboxyl-terminal serine-protease-like domain (Figure 17.1a). Unlike other plasminogen family members, HGF has no proteolytic activity (1). The HGF N and K1 domains contain the primary Met binding sites (12), and the protease-like domain contains an important secondary Met binding site (13). Proteolytic processing of the single-chain HGF precursor results in the active disulfide-linked heterodimer; the amino-terminal α-chain contains N and K1–4, and the β-chain contains the protease-like region (1).