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HGF

Official Full Name
hepatocyte growth factor
Organism
Homo sapiens
GeneID
3082
Background
This gene encodes a protein that binds to the hepatocyte growth factor receptor to regulate cell growth, cell motility and morphogenesis in numerous cell and tissue types. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate alpha and beta chains, which form the mature heterodimer. This protein is secreted by mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. This protein also plays a role in angiogenesis, tumorogenesis, and tissue regeneration. Although the encoded protein is a member of the peptidase S1 family of serine proteases, it lacks peptidase activity. Mutations in this gene are associated with nonsyndromic hearing loss. [provided by RefSeq, Nov 2015]
Synonyms
SF; HGFB; HPTA; F-TCF; DFNB39;
Bio Chemical Class
Peptidase
Protein Sequence
MWVTKLLPALLLQHVLLHLLLLPIAIPYAEGQRKRRNTIHEFKKSAKTTLIKIDPALKIKTKKVNTADQCANRCTRNKGLPFTCKAFVFDKARKQCLWFPFNSMSSGVKKEFGHEFDLYENKDYIRNCIIGKGRSYKGTVSITKSGIKCQPWSSMIPHEHSFLPSSYRGKDLQENYCRNPRGEEGGPWCFTSNPEVRYEVCDIPQCSEVECMTCNGESYRGLMDHTESGKICQRWDHQTPHRHKFLPERYPDKGFDDNYCRNPDGQPRPWCYTLDPHTRWEYCAIKTCADNTMNDTDVPLETTECIQGQGEGYRGTVNTIWNGIPCQRWDSQYPHEHDMTPENFKCKDLRENYCRNPDGSESPWCFTTDPNIRVGYCSQIPNCDMSHGQDCYRGNGKNYMGNLSQTRSGLTCSMWDKNMEDLHRHIFWEPDASKLNENYCRNPDDDAHGPWCYTGNPLIPWDYCPISRCEGDTTPTIVNLDHPVISCAKTKQLRVVNGIPTRTNIGWMVSLRYRNKHICGGSLIKESWVLTARQCFPSRDLKDYEAWLGIHDVHGRGDEKCKQVLNVSQLVYGPEGSDLVLMKLARPAVLDDFVSTIDLPNYGCTIPEKTSCSVYGWGYTGLINYDGLLRVAHLYIMGNEKCSQHHRGKVTLNESEICAGAEKIGSGPCEGDYGGPLVCEQHKMRMVLGVIVPGRGCAIPNRPGIFVRVAYYAKWIHKIILTYKVPQS
Open
Disease
Acute myeloid leukaemia, Angina pectoris, Brain cancer, Chronic arterial occlusive disease, Diabetic foot ulcer, Graft-versus-host disease, Lung cancer, Lymphoma, Motor neuron disease, Multiple myeloma, Neuropathy, Pancreatic cancer, Peripheral Ischemic Ulcers, Solid tumour/cancer, Squamous cell carcinoma
Approved Drug
0
Clinical Trial Drug
8 +
Discontinued Drug
1 +

Detailed Information

The hepatocyte growth factor (HGF) represents a remarkable example of molecular complexity in cellular signaling. First discovered in rat plasma in 1984, HGF exists as a sophisticated heterodimeric molecule comprising a 69kDa α-chain and a 34kDa β-chain. The α-chain features a distinctive hairpin structure at its N-terminus, while the β-chain contains a serine protease-like domain. Despite its structural similarity to serine proteases, HGF lacks enzymatic activity, instead functioning as a versatile signaling molecule that orchestrates numerous cellular processes.

When HGF binds to its receptor c-Met, it initiates a cascade of molecular events that begins with receptor dimerization and subsequent tyrosine phosphorylation. This activation triggers multiple downstream signaling pathways, including PI3K-AKT, Ras-MAPK, STAT, and Wnt/β-catenin cascades. Through these pathways, HGF regulates diverse cellular behaviors, from proliferation and migration to survival and morphogenesis. The protein's influence extends across various tissue types, where it acts through both paracrine and autocrine mechanisms to coordinate complex cellular responses.

Figure 1 provides an overview of the HGF/MET signaling pathway, highlighting its biological functions and implications in various physiological and pathological processes.Figure 1. Overview of the HGF/MET Signaling Pathway and Its Targeted Therapy. (Moosavi, F. et. al., 2021)

Developmental and Physiological Functions

HGF/c-Met signaling regulates cell organization and tissue formation throughout embryonic development. The path coordinates skeletal muscle development, guides mesenchymal stem cell migration, and promotes brain tissue growth. HGF/c-Met signaling maintains adult stem cells functioning and helps to maintain the balance of numerous specialized cells, like heart muscle cells, pancreatic β cells, and hepatocytes in adult tissues, thereby continuing this function in development.

In many various methods, HGF mends injuries and repairs damaged tissues in formed tissues. By modulating fibroblast activity, the protein prevents damage from becoming too severe and promotes blood vessel formation, which enables tissues to repair by extending cell life. How well epithelial and mesenchymal tissues cooperate will determine these duties. HGF is a major driver of intercellular communication.

Cancer Development and Progression

The role of HGF/c-Met signaling in cancer represents a compelling example of how normal physiological processes can be hijacked during disease development. Cancer cells often exploit this pathway by secreting excessive amounts of HGF into the tumor microenvironment (TME), creating a self-perpetuating cycle of growth and invasion. This process begins with cancer cells producing HGF, which activates c-Met receptors on both tumor cells and surrounding stromal cells. This leads to increased HGF production and creates a positive feedback loop that supports tumor growth.

The pathway's influence on cancer stem cells (CSCs) particularly highlights its significance in tumor progression. In pancreatic cancer, HGF/c-Met signaling helps maintain CSC populations by regulating their metabolic preferences. In colorectal cancer, the pathway drives abnormal Wnt/β-catenin signaling, promoting metastasis. Hepatocellular carcinoma shows a distinctive pattern where cancer-associated fibroblasts utilize c-Met/FRA1/HEY1 signaling to support CSC self-renewal.

Tumor Microenvironment and Angiogenesis

HGF/c-Met signaling regulates a complex network of cell contacts in the vicinity of a tumor that supports its growth. The path is very effective in several respects for promoting angiogenesis. It raises VEGFA production and lowers the effectiveness of natural angiogenesis inhibitors such as thrombospondin 1. HGF also promotes the growth and development of vascular stem cells, which directly support the formation of new blood vessels.

The path influences more than only the development of blood vessels; it also influences how stroma and tumors interact in a larger context. Cancer-related fibroblasts produce more HGF when they detect signals from the stroma. This further alters the local environment to assist the tumor in growing. With HGF/c-Met signals being rather important, this creates a complicated situation at the molecular level where cancer cells and stromal cells communicate constantly.

Therapeutic Implications and Future Directions

Treatment has become a hot topic because HGF/c-Met signaling is so crucial in cancer. By use of many c-Met blockers including Crizotinib, this communication method has been proven to hold promise in the sector. However, given the complexity of cancer biology, treating HGF/c-Met would not be sufficient to provide the optimal outcomes from therapy.

Recent research has shown intriguing connections between HGF/c-Met signaling and how medications no longer perform as they once did. For instance, in non-small cell lung cancer, alterations in metabolism involving HGF signaling might reduce the efficacy of EGFR medications. These findings have led to the development of more sophisticated cancer treatment strategies including combination therapies that simultaneously target many pathways.

Much clinical research investigating novel treatment approaches will help the sector to evolve in the future. Some of this research seeks novel pharmaceutical choices aimed at various areas of the HGF/c-Met pathway. Others examine how this route interacts with other significant signaling networks, including EGF and VEGF. Our knowledge of these complex biological processes is helping us to move closer to more efficient and particular cancer therapies that can better address the issues of tumor diversity and drug resistance.

References:

  1. Raghav KP, Gonzalez-Angulo AM, et al. Role of HGF/MET axis in resistance of lung cancer to contemporary management. Transl Lung Cancer Res. 2012;1(3):179-193.
  2. Zambelli A, Biamonti G, Amato A. HGF/c-Met Signalling in the Tumor Microenvironment. Adv Exp Med Biol. 2021;1270:31-44.
  3. Moosavi F, Giovannetti E, Peters GJ, et al. Combination of HGF/MET-targeting agents and other therapeutic strategies in cancer. Crit Rev Oncol Hematol. 2021;160:103234.
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