Hepatocyte Growth Factor

Polypeptide growth factors have been intensively studied since their initial discovery as pivotal regulators of cell proliferation and differentiation in multicellular organisms more than 70 years ago. Despite their name, many elicit multiple cellular responses during embryogenesis and throughout adulthood; dysregulated signaling can also contribute to disease. Few factors illustrate these principles as thoroughly as hepatocyte growth factor (Hgf), also known as scatter factor (SF). As evident from its pseudonyms, Hgf pleiotropism has been a striking feature from its initial discovery more than two decades ago by several groups with interests in liver regeneration, cell growth control, motility and morphogenesis. Thousands of scientific publications now document the critical contributions of Hgf signaling to normal development, adult homeostasis and several forms of cancer. Hgf protein and the related macrophage stimulating protein (MSP; also known as Hgf-like protein) comprise a small but distinct growth factor subfamily related to plasminogen serine proteinases, though they are devoid of proteolytic activity. In humans, a single gene encodes five HGF isoforms produced through mRNA splicing: two full-length forms that differ by only five residues and three substantially shorter forms. The more abundant full-length forms are secreted as inactive single chain polypeptides that are proteolytically converted to biologically active disulfide-linked heterodimers at the target cell surface. All isoforms bind strongly to heparan sulfate proteoglycan, a feature that profoundly influences their local and systemic distribution, receptor binding, and biological impact. Hgf signaling is primarily paracrine: it is secreted by mesenchymal cells in many tissues and acts on a broad spectrum of cellular targets that express the receptor tyrosine kinase known as Met. Hgf-related research has identified molecular pathways important for tissue protection, tissue regeneration and oncogenesis, with the promise to advance tissue engineering, regenerative medicine as well as cancer diagnosis and treatment.This work was supported by National Institutes of Health (USA) grants Z01 BC005626 and ZIA BC011124 to D. P. Bottaro