Hepatocyte growth factor (HGF) or scatter factor (SF) is a paracrine cellular growth, motility and morphogenic factor. It is secreted by mesenchymal cells and targets and acts primarily upon epithelial cells and endothelial cells, but also acts on haemopoietic progenitor cells and T cells. It has been shown to have a major role in embryonic organ development, specifically in myogenesis, in adult organ regeneration, and in wound healing.[5]
Quick Facts HGF, Available structures ...
| HGF |
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| Available structures |
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| PDB | Ortholog search: PDBe RCSB |
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| List of PDB id codes |
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1BHT, 1GMN, 1GMO, 1GP9, 1NK1, 1SHY, 1SI5, 2HGF, 2QJ2, 3HMS, 3HMT, 3HN4, 3MKP, 3SP8, 4K3J, 4O3T, 4O3U, 5COE, 5CP9, 5CS1, 5CS3, 5CS5, 5CS9, 5CSQ, 5CT1, 5CT2, 5CT3, 4D3C |
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| Aliases | HGF, DFNB39, F-TCF, HGFB, HPTA, SF, hepatocyte growth factor |
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| External IDs | OMIM: 142409; MGI: 96079; HomoloGene: 503; GeneCards: HGF; OMA:HGF - orthologs |
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Hepatocyte growth factor regulates cell growth, cell motility, and morphogenesis by activating a tyrosine kinase signaling cascade after binding to the proto-oncogenic c-Met receptor.[6][7] Hepatocyte growth factor is secreted by platelets,[8] and mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. Its ability to stimulate mitogenesis, cell motility, and matrix invasion gives it a central role in angiogenesis, tumorogenesis, and tissue regeneration.[9]
It is secreted as a single inactive polypeptide and is cleaved by serine proteases into a 69-kDa alpha-chain and 34-kDa beta-chain. A disulfide bond between the alpha and beta chains produces the active, heterodimeric molecule. The protein belongs to the plasminogen subfamily of S1 peptidases but has no detectable protease activity.[9]
Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[10][11]
As well as the well-characterised effects of HGF on epithelial cells, endothelial cells and haemopoietic progenitor cells, HGF also regulates the chemotaxis of T cells into heart tissue. Binding of HGF by c-Met, expressed on T cells, causes the upregulation of c-Met, CXCR3, and CCR4 which in turn imbues them with the ability to migrate into heart tissue.[12] HGF also promotes angiogenesis in ischemia injury.[13]
HGF may further play a role as an indicator for prognosis of chronicity for Chikungunya virus induced arthralgia. High HGF levels correlate with high rates of recovery.[14]
Excessive local expression of HGF in the breasts has been implicated in macromastia.[15] HGF is also importantly involved in normal mammary gland development.[16][17]
HGF has been implicated in a variety of cancers, including of the lungs, pancreas, thyroid, colon, and breast.[18][19][20]
Increased expression of HGF has been associated with the enhanced and scarless wound healing capabilities of fibroblast cells isolated from the oral mucosa tissue.[21]
Circulating plasma levels
Plasma from patients with advanced heart failure presents increased levels of HGF, which correlates with a negative prognosis and a high risk of mortality.[22][23] Circulating HGF has been also identified as a prognostic marker of severity in patients with hypertension.[24] Circulating HGF has been also suggested as a precocious biomarker for the acute phase of bowel inflammation.[25]
Exogenous HGF administered by intravenous injection is cleared rapidly from circulation by the liver, with a half-life of approximately 4 minutes.[26][27][28][29]
Dihexa is an orally active, centrally penetrant small-molecule compound that directly binds to HGF and potentiates its ability to activate its receptor, c-Met.[30] It is a strong inducer of neurogenesis and is being studied for the potential treatment of Alzheimer's disease and Parkinson's disease.[31][32]
Hepatocyte growth factor has been shown to interact with the protein product of the c-Met oncogene, identified as the HGF receptor (HGFR).[6][33][34] Both overexpression of the Met/HGFR receptor protein and autocrine activation of Met/HGFR by simultaneous expression of the hepatocyte growth factor ligand have been implicated in oncogenesis.[35][36]
Hepatocyte growth factor interacts with the sulfated glycosaminoglycans heparan sulfate and dermatan sulfate.[37][38] The interaction with heparan sulfate allows hepatocyte growth factor to form a complex with c-Met that is able to transduce intracellular signals leading to cell division and cell migration.[37][39]
Gallagher JT, Lyon M (2000). "Molecular structure of Heparan Sulfate and interactions with growth factors and morphogens". In Iozzo MV (ed.). Proteoglycans: structure, biology and molecular interactions. Marcel Dekker Inc. New York, New York. pp. 27–59.
Yang ZJ, Zhang YR, Chen B, Zhang SL, Jia EZ, Wang LS, et al. (July 2009). "Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease". Molecular Biology Reports. 36 (6): 1323–1329. doi:10.1007/s11033-008-9315-3. PMID 18649012. S2CID 23419866. Hahn W, Pyun WB, Kim DS, Yoo WS, Lee SD, Won JH, et al. (October 2011). "Enhanced cardioprotective effects by coexpression of two isoforms of hepatocyte growth factor from naked plasmid DNA in a rat ischemic heart disease model". The Journal of Gene Medicine. 13 (10): 549–555. doi:10.1002/jgm.1603. PMID 21898720. S2CID 26812780. Niranjan B, Buluwela L, Yant J, Perusinghe N, Atherton A, Phippard D, et al. (September 1995). "HGF/SF: a potent cytokine for mammary growth, morphogenesis and development". Development. 121 (9): 2897–2908. doi:10.1242/dev.121.9.2897. PMID 7555716. Kamalati T, Niranjan B, Yant J, Buluwela L (January 1999). "HGF/SF in mammary epithelial growth and morphogenesis: in vitro and in vivo models". Journal of Mammary Gland Biology and Neoplasia. 4 (1): 69–77. doi:10.1023/A:1018756620265. PMID 10219907. S2CID 9310133. Richter B, Koller L, Hohensinner PJ, Zorn G, Brekalo M, Berger R, et al. (September 2013). "A multi-biomarker risk score improves prediction of long-term mortality in patients with advanced heart failure". International Journal of Cardiology. 168 (2): 1251–1257. doi:10.1016/j.ijcard.2012.11.052. PMID 23218577. Rychli K, Richter B, Hohensinner PJ, Kariem Mahdy A, Neuhold S, Zorn G, et al. (July 2011). "Hepatocyte growth factor is a strong predictor of mortality in patients with advanced heart failure". Heart. 97 (14): 1158–1163. doi:10.1136/hrt.2010.220228. PMID 21572126. S2CID 22426278. Nakamura S, Morishita R, Moriguchi A, Yo Y, Nakamura Y, Hayashi S, et al. (December 1998). "Hepatocyte growth factor as a potential index of complication in diabetes mellitus". Journal of Hypertension. 16 (12 Pt 2): 2019–2026. doi:10.1097/00004872-199816121-00025. PMID 9886892. S2CID 6615179. Appasamy R, Tanabe M, Murase N, Zarnegar R, Venkataramanan R, Van Thiel DH, et al. (March 1993). "Hepatocyte growth factor, blood clearance, organ uptake, and biliary excretion in normal and partially hepatectomized rats". Laboratory Investigation; A Journal of Technical Methods and Pathology. 68 (3): 270–276. PMID 8450646. Kato Y, Liu KX, Nakamura T, Sugiyama Y (August 1994). "Heparin-hepatocyte growth factor complex with low plasma clearance and retained hepatocyte proliferating activity". Hepatology. 20 (2): 417–424. doi:10.1002/hep.1840200223. PMID 8045504. S2CID 20021569. Benoist CC, Kawas LH, Zhu M, Tyson KA, Stillmaker L, Appleyard SM, et al. (November 2014). "The procognitive and synaptogenic effects of angiotensin IV-derived peptides are dependent on activation of the hepatocyte growth factor/c-met system". The Journal of Pharmacology and Experimental Therapeutics. 351 (2): 390–402. doi:10.1124/jpet.114.218735. PMC 4201273. PMID 25187433. (This paper currently has an expression of concern, see doi:10.1124/jpet.114.218735concern, PMID 34551987, Retraction Watch. If this is an intentional citation to a such a paper, please replace {{expression of concern|...}} with {{expression of concern|...|intentional=yes}}.) Wright JW, Harding JW (2015). "The Brain Hepatocyte Growth Factor/c-Met Receptor System: A New Target for the Treatment of Alzheimer's Disease". Journal of Alzheimer's Disease. 45 (4): 985–1000. doi:10.3233/JAD-142814. PMID 25649658. Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". Exs. 65: 131–165. PMID 8380735. Johnson M, Koukoulis G, Kochhar K, Kubo C, Nakamura T, Iyer A (September 1995). "Selective tumorigenesis in non-parenchymal liver epithelial cell lines by hepatocyte growth factor transfection". Cancer Letters. 96 (1): 37–48. doi:10.1016/0304-3835(95)03915-j. PMID 7553606. Kochhar KS, Johnson ME, Volpert O, Iyer AP (1995). "Evidence for autocrine basis of transformation in NIH-3T3 cells transfected with met/HGF receptor gene". Growth Factors. 12 (4): 303–313. doi:10.3109/08977199509028968. PMID 8930021.
- Michalopoulos GK, Zarnegav R (January 1992). "Hepatocyte growth factor". Hepatology. 15 (1): 149–155. doi:10.1002/hep.1840150125. PMID 1530787. S2CID 39873193.
- Nakamura T (1992). "Structure and function of hepatocyte growth factor". Progress in Growth Factor Research. 3 (1): 67–85. doi:10.1016/0955-2235(91)90014-U. PMID 1838014.
- Ware LB, Matthay MA (May 2002). "Keratinocyte and hepatocyte growth factors in the lung: roles in lung development, inflammation, and repair". American Journal of Physiology. Lung Cellular and Molecular Physiology. 282 (5): L924–L940. doi:10.1152/ajplung.00439.2001. PMID 11943656. S2CID 22175256.
- Funakoshi H, Nakamura T (January 2003). "Hepatocyte growth factor: from diagnosis to clinical applications". Clinica Chimica Acta; International Journal of Clinical Chemistry. 327 (1–2): 1–23. doi:10.1016/S0009-8981(02)00302-9. PMID 12482615.
- Skibinski G (2004). "The role of hepatocyte growth factor/c-met interactions in the immune system". Archivum Immunologiae et Therapiae Experimentalis. 51 (5): 277–282. PMID 14626426.
- Kalluri R, Neilson EG (December 2003). "Epithelial-mesenchymal transition and its implications for fibrosis". The Journal of Clinical Investigation. 112 (12): 1776–1784. doi:10.1172/JCI20530. PMC 297008. PMID 14679171.
- Hurle RA, Davies G, Parr C, Mason MD, Jenkins SA, Kynaston HG, et al. (October 2005). "Hepatocyte growth factor/scatter factor and prostate cancer: a review". Histology and Histopathology. 20 (4): 1339–1349. doi:10.14670/HH-20.1339. PMID 16136515.
- Kemp LE, Mulloy B, Gherardi E (June 2006). "Signalling by HGF/SF and Met: the role of heparan sulphate co-receptors". Biochemical Society Transactions. 34 (Pt 3): 414–417. doi:10.1042/BST0340414. PMID 16709175. S2CID 31340761.
- Ejaz A, Epperly MW, Hou W, Greenberger JS, Rubin JP (June 2019). "Adipose-Derived Stem Cell Therapy Ameliorates Ionizing Irradiation Fibrosis via Hepatocyte Growth Factor-Mediated Transforming Growth Factor-β Downregulation and Recruitment of Bone Marrow Cells". Stem Cells. 37 (6): 791–802. doi:10.1002/stem.3000. PMC 8457883. PMID 30861238.
