Hepatocyte Growth Factor (HGF) is a potent multifunctional protein primarily involved in cell growth, regeneration, and repair. It is originally identified as a factor promoting the proliferation of hepatocytes (liver cells) but has since been recognized for its broader roles in various tissues and processes, including embryonic development, wound healing, and cancer.

• Structure:
  • Molecular Composition: HGF is a heterodimeric protein consisting of an α-chain and a β-chain linked by a disulfide bond. The mature form of HGF has a molecular weight of approximately 80 kDa.
  • Domain Structure: HGF is composed of four distinct domains:
    • N-terminal Domain (Kunitz-like Domain): Contains a domain that inhibits serine proteases.
    • Kringle Domains (1 and 2): These domains are involved in receptor binding and exhibit similarity to the kringle domains of other proteins, such as plasminogen.
    • Catalytic Domain: Includes a serine protease-like domain that is critical for biological activity.
  • Pro-HGF Activation: HGF is initially synthesized as an inactive precursor (pro-HGF) and must be activated by proteolytic cleavage to become biologically active.
• Receptor Binding and Signaling:
  • HGF Receptor (c-Met): HGF exerts its effects by binding to the c-Met receptor, a receptor tyrosine kinase. The c-Met receptor is composed of an extracellular ligand-binding domain, a single transmembrane domain, and an intracellular tyrosine kinase domain.
  • Activation Mechanism: Binding of HGF to c-Met induces receptor dimerization and autophosphorylation of tyrosine residues in the intracellular domain. This activation initiates several downstream signaling pathways.
  • Signal Transduction Pathways:
    • PI3K/AKT Pathway: Promotes cell survival, growth, and metabolism.
    • MAPK/ERK Pathway: Regulates cell proliferation, differentiation, and motility.
    • SRC Pathway: Involves Src family kinases in regulating cell movement and invasion.
• Biological Functions:
  • Cell Proliferation and Survival: HGF stimulates the proliferation of various cell types, including hepatocytes, endothelial cells, epithelial cells, and fibroblasts. It also promotes cell survival by inhibiting apoptosis.
  • Wound Healing: HGF plays a crucial role in wound healing by enhancing cell migration, proliferation, and tissue remodeling. It stimulates the repair of damaged tissues, including skin, liver, and other organs.
  • Liver Regeneration: Initially discovered as a liver-specific growth factor, HGF is critical for liver regeneration following injury or partial hepatectomy. It promotes hepatocyte proliferation and liver tissue repair.
  • Angiogenesis: HGF has angiogenic properties, promoting the formation of new blood vessels by stimulating endothelial cell proliferation and migratio
• Applications in Research and Medicine:
  • Regenerative Medicine: HGF is investigated for its potential to promote tissue regeneration and repair in conditions such as liver cirrhosis, myocardial infarction, and peripheral artery disease.
  • Cancer Research: Aberrant HGF/c-Met signaling is associated with tumor growth, invasion, and metastasis. Targeting the HGF/c-Met pathway is a strategy for developing cancer therapies, particularly in cancers such as lung, gastric, and liver cancers.
  • Wound Healing Therapies: HGF is explored as a therapeutic agent to enhance wound healing in chronic wounds, ulcers, and burns, due to its ability to stimulate cell migration and proliferation.
• Clinical Implications:
  • Liver Diseases: HGF is considered a potential therapeutic agent for liver diseases such as hepatitis, cirrhosis, and liver failure due to its role in promoting hepatocyte proliferation and liver regeneration.
  • Cancer Treatment: Inhibitors of HGF or c-Met are being developed to target tumors with aberrant HGF/c-Met signaling. These inhibitors aim to block tumor growth, metastasis, and resistance to other treatments.
  • Cardiovascular Diseases: HGF's ability to promote angiogenesis and tissue repair makes it a candidate for treating cardiovascular diseases such as heart attacks and peripheral vascular disease.