Hepatocyte growth factor

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.[4]

HGF
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 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
Identifiers
Aliases	HGF, DFNB39, F-TCF, HGFB, HPTA, SF, hepatocyte growth factor
External IDs	OMIM: 142409 MGI: 96079 HomoloGene: 503 GeneCards: HGF
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q21.11 Start 81,699,010 bp[1] End 81,770,438 bp[1]
RNA expression pattern More reference expression data
Gene ontology Molecular function • GO:0001948 protein binding • identical protein binding • chemoattractant activity • protein heterodimerization activity • growth factor activity • serine-type endopeptidase activity • protein tyrosine kinase activity • Ras guanyl-nucleotide exchange factor activity • phosphatidylinositol-4,5-bisphosphate 3-kinase activity Cellular component • membrane • extracellular region • platelet alpha granule lumen • extracellular Biological process • negative regulation of cysteine-type endopeptidase activity involved in apoptotic process • negative regulation of hydrogen peroxide-mediated programmed cell death • positive regulation of neuron projection regeneration • positive regulation of interleukin-10 production • positive regulation of cell migration • cellular response to hepatocyte growth factor stimulus • negative regulation of release of cytochrome c from mitochondria • negative regulation of interleukin-6 production • platelet degranulation • negative regulation of apoptotic process • regulation of branching involved in salivary gland morphogenesis by mesenchymal-epithelial signaling • positive regulation of angiogenesis • positive regulation of myelination • positive regulation of osteoblast differentiation • activation of MAPK activity • myoblast proliferation • negative regulation of extrinsic apoptotic signaling pathway via death domain receptors • animal organ regeneration • cell morphogenesis • positive regulation of cell proliferation • hyaluronan metabolic process • positive regulation of DNA biosynthetic process • negative regulation of peptidyl-serine phosphorylation • epithelial–mesenchymal transition • positive regulation of peptidyl-tyrosine phosphorylation • cell chemotaxis • liver development • positive regulation of phosphatidylinositol 3-kinase signaling • regulation of p38MAPK cascade • cellular proliferation • negative regulation of autophagy • hepatocyte growth factor receptor signaling pathway • negative regulation of inflammatory response • positive regulation of transcription from RNA polymerase II promoter • regulation of tau-protein kinase activity • proteolysis • positive chemotaxis • MAPK cascade • peptidyl-tyrosine phosphorylation • phosphatidylinositol phosphorylation • GO:0007067 mitotic cell cycle • regulation of receptor activity • positive regulation of protein kinase B signaling • positive regulation of protein phosphorylation • cytokine-mediated signaling pathway • epithelial cell proliferation Sources:Amigo / QuickGO
Orthologs
Species	Human	Mouse
Entrez	3082	15234
Ensembl	ENSG00000019991	ENSMUSG00000028864
UniProt	P14210	Q08048
RefSeq (mRNA)	NM_000601 NM_001010931 NM_001010932 NM_001010933 NM_001010934	NM_010427 NM_001289458 NM_001289459 NM_001289460 NM_001289461
RefSeq (protein)	NP_000592 NP_001010931 NP_001010932 NP_001010933 NP_001010934	NP_001276387 NP_001276388 NP_001276389 NP_001276390 NP_034557
Location (UCSC)	Chr 7: 81.7 – 81.77 Mb	n/a
PubMed search	[2]	[3]
Wikidata
View/Edit Human View/Edit Mouse

Function

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.[5][6] Hepatocyte growth factor is secreted by 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.[7]

Structure

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.[7]

Clinical significance

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.[8][9] 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.[10] HGF also promotes angiogenesis in ischemia injury.[11] 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.[12]

Excessive local expression of HGF in the breasts has been implicated in macromastia.[13] HGF is also importantly involved in normal mammary gland development.[14][15]

HGF has been implicated in a variety of cancers, including of the lungs, pancreas, thyroid, colon, and breast.[16][17][18]

Increased expression of HGF has been associated with the enhanced and scarless wound healing capabilities of fibroblast cells isolated from the oral mucosa tissue.[19]

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.[20][21] Circulating HGF has been also identified as a prognostic marker of severity in patients suffering from hypertension.[22] Circulating HGF has been also suggested as a precocious biomarker for the acute phase of bowel inflammation.[23]

Pharmacokinetics

Exogenous HGF administered by intravenous injection is cleared rapidly from circulation by the liver, with a half-life of approximately 4 minutes.[24][25][26][27]

Modulators

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.[28] It is a strong inducer of neurogenesis and is being studied for the potential treatment of Alzheimer's disease and Parkinson's disease.[29][30]

Interactions

Hepatocyte growth factor has been shown to interact with the protein product of the c-Met oncogene, identified as the HGF receptor (HGFR).[5][31][32] 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.[33][34] Hepatocyte growth factor interacts with the sulfated glycosaminoglycans heparan sulfate and dermatan sulfate.[35][36] 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.[35][37]

See also

• Epidermal growth factor
• Insulin-like growth factor 1
• Epithelial–mesenchymal transition
• Madin-Darby Canine Kidney Cells

References

1. GRCh38: Ensembl release 89: ENSG00000019991 - Ensembl, May 2017
2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. Gallagher, J.T., Lyon, M. (2000). "Molecular structure of Heparan Sulfate and interactions with growth factors and morphogens". In Iozzo, M, V. (ed.). Proteoglycans: structure, biology and molecular interactions. Marcel Dekker Inc. New York, New York. pp. 27–59.CS1 maint: multiple names: authors list (link)
5. Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, Aaronson SA (February 1991). "Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product". Science. 251 (4995): 802–4. Bibcode:1991Sci...251..802B. doi:10.1126/science.1846706. PMID 1846706.
6. Johnson M, Koukoulis G, Matsumoto K, Nakamura T, Iyer A (June 1993). "Hepatocyte growth factor induces proliferation and morphogenesis in nonparenchymal epithelial liver cells". Hepatology. 17 (6): 1052–61. doi:10.1016/0270-9139(93)90122-4. PMID 8514254.
7. "Entrez Gene: HGF hepatocyte growth factor (hepapoietin A; scatter factor)".
8. Yang ZJ, Zhang YR, Chen B, Zhang SL, Jia EZ, Wang LS, Zhu TB, Li CJ, Wang H, Huang J, Cao KJ, Ma WZ, Wu B, Wang LS, Wu CT (July 2009). "Phase I clinical trial on intracoronary administration of Ad-hHGF treating severe coronary artery disease". Molecular Biology Reports. 36 (6): 1323–9. doi:10.1007/s11033-008-9315-3. PMID 18649012. S2CID 23419866.
9. Hahn W, Pyun WB, Kim DS, Yoo WS, Lee SD, Won JH, Shin GJ, Kim JM, Kim S (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): 549–55. doi:10.1002/jgm.1603. PMID 21898720. S2CID 26812780.
10. Komarowska I, Coe D, Wang G, Haas R, Mauro C, Kishore M, Cooper D, Nadkarni S, Fu H, Steinbruchel DA, Pitzalis C, Anderson G, Bucy P, Lombardi G, Breckenridge R, Marelli-Berg FM (September 2016). "Hepatocyte Growth Factor Receptor c-Met Instructs T Cell Cardiotropism and Promotes T Cell Migration to the Heart via Autocrine Chemokine Release". Immunity. 42 (6): 1087–99. doi:10.1016/j.immuni.2015.05.014. PMC 4510150. PMID 26070483.
11. Chang HK, Kim PH, Cho, HM, Yum, SY, Choi, YJ, Lee D, Kang I, Kang KS, Jang G, Cho JY (Sep 2016). "Inducible HGF-secreting Human Umbilical Cord Blood-derived MSCs Produced via TALEN-mediated Genome Editing Promoted Angiogenesis". Molecular Therapy. 24 (9): 1644–54. doi:10.1038/mt.2016.120. PMC 5113099. PMID 27434585.
12. Chow A, Her Z, Ong EK, Chen JM, Dimatatac F, Kwek DJ, Barkham T, Yang H, Rénia L, Leo YS, Ng LF (January 2011). "Persistent arthralgia induced by Chikungunya virus infection is associated with interleukin-6 and granulocyte macrophage colony-stimulating factor". The Journal of Infectious Diseases. 203 (2): 149–57. doi:10.1093/infdis/jiq042. PMC 3071069. PMID 21288813.
13. Zhong A, Wang G, Yang J, Xu Q, Yuan Q, Yang Y, Xia Y, Guo K, Horch RE, Sun J (July 2014). "Stromal-epithelial cell interactions and alteration of branching morphogenesis in macromastic mammary glands". Journal of Cellular and Molecular Medicine. 18 (7): 1257–66. doi:10.1111/jcmm.12275. PMC 4124011. PMID 24720804.
14. Niranjan B, Buluwela L, Yant J, Perusinghe N, Atherton A, Phippard D, Dale T, Gusterson B, Kamalati T (1995). "HGF/SF: a potent cytokine for mammary growth, morphogenesis and development". Development. 121 (9): 2897–908. PMID 7555716.
15. Kamalati T, Niranjan B, Yant J, Buluwela L (1999). "HGF/SF in mammary epithelial growth and morphogenesis: in vitro and in vivo models". J Mammary Gland Biol Neoplasia. 4 (1): 69–77. doi:10.1023/A:1018756620265. PMID 10219907. S2CID 9310133.
16. Thomas R. Ziegler; Glenn F. Pierce; David N. Herndon (6 December 2012). Growth Factors and Wound Healing: Basic Science and Potential Clinical Applications. Springer Science & Business Media. pp. 311–. ISBN 978-1-4612-1876-0.
17. Sheen-Chen SM, Liu YW, Eng HL, Chou FF (March 2005). "Serum levels of hepatocyte growth factor in patients with breast cancer". Cancer Epidemiology, Biomarkers & Prevention. 14 (3): 715–7. doi:10.1158/1055-9965.EPI-04-0340. PMID 15767355. S2CID 3089594.
18. El-Attar HA, Sheta MI (2011). "Hepatocyte growth factor profile with breast cancer". Indian Journal of Pathology & Microbiology. 54 (3): 509–13. doi:10.4103/0377-4929.85083. PMID 21934211.
19. Dally J, Khan JS, Voisey A, Charalambous C, John HL, Woods EL, Steadman R, Moseley R, Midgley AC (August 2017). "Hepatocyte Growth Factor Mediates Enhanced Wound Healing Responses and Resistance to Transforming Growth Factor-β₁-Driven Myofibroblast Differentiation in Oral Mucosal Fibroblasts". International Journal of Molecular Sciences. 18 (9): 1843. doi:10.3390/ijms18091843. PMC 5618492. PMID 28837064.
20. Richter B, Koller L, Hohensinner PJ, Zorn G, Brekalo M, Berger R, Mörtl D, Maurer G, Pacher R, Huber K, Wojta J, Hülsmann M, Niessner A (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): 1251–7. doi:10.1016/j.ijcard.2012.11.052. PMID 23218577.
21. Rychli K, Richter B, Hohensinner PJ, Kariem Mahdy A, Neuhold S, Zorn G, Berger R, Mörtl D, Huber K, Pacher R, Wojta J, Niessner A, Hülsmann M (July 2011). "Hepatocyte growth factor is a strong predictor of mortality in patients with advanced heart failure". Heart. 97 (14): 1158–63. doi:10.1136/hrt.2010.220228. PMID 21572126. S2CID 22426278.
22. Nakamura S, Morishita R, Moriguchi A, Yo Y, Nakamura Y, Hayashi S, Matsumoto K, Matsumoto K, Nakamura T, Higaki J, Ogihara T (December 1998). "Hepatocyte growth factor as a potential index of complication in diabetes mellitus". Journal of Hypertension. 16 (12 Pt 2): 2019–26. doi:10.1097/00004872-199816121-00025. PMID 9886892. S2CID 6615179.
23. Sorour AE, Lönn J, Nakka SS, Nayeri T, Nayeri F (January 2015). "Evaluation of hepatocyte growth factor as a local acute phase response marker in the bowel: the clinical impact of a rapid diagnostic test for immediate identification of acute bowel inflammation". Cytokine. 71 (1): 8–15. doi:10.1016/j.cyto.2014.07.255. PMID 25174881.
24. Yang J, Chen S, Huang L, Michalopoulos GK, Liu Y (April 2001). "Sustained expression of naked plasmid DNA encoding hepatocyte growth factor in mice promotes liver and overall body growth". Hepatology. 33 (4): 848–59. doi:10.1053/jhep.2001.23438. PMC 1821076. PMID 11283849.
25. Appasamy R, Tanabe M, Murase N, Zarnegar R, Venkataramanan R, Van Thiel DH, Michalopoulos GK (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): 270–6. PMID 8450646.
26. 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): 417–24. doi:10.1002/hep.1840200223. PMID 8045504. S2CID 20021569.
27. Yu Y, Yao AH, Chen N, Pu LY, Fan Y, Lv L, Sun BC, Li GQ, Wang XH (July 2007). "Mesenchymal stem cells over-expressing hepatocyte growth factor improve small-for-size liver grafts regeneration". Molecular Therapy. 15 (7): 1382–9. doi:10.1038/sj.mt.6300202. PMID 17519892.
28. Benoist CC, Kawas LH, Zhu M, Tyson KA, Stillmaker L, Appleyard SM, Wright JW, Wayman GA, Harding JW (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.
29. 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.
30. Wright JW, Kawas LH, Harding JW (February 2015). "The development of small molecule angiotensin IV analogs to treat Alzheimer's and Parkinson's diseases". Progress in Neurobiology. 125: 26–46. doi:10.1016/j.pneurobio.2014.11.004. PMID 25455861. S2CID 41360989.
31. Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". Exs. 65: 131–65. PMID 8380735.
32. Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, Narsimhan RP, Hartmann G, Zarnegar R, Michalopoulos GK (October 1991). "Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor". The EMBO Journal. 10 (10): 2867–78. doi:10.1002/j.1460-2075.1991.tb07836.x. PMC 452997. PMID 1655405.
33. 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.
34. 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): 303–13. doi:10.3109/08977199509028968. PMID 8930021.
35. Lyon M, Deakin JA, Gallagher JT (January 2002). "The mode of action of heparan and dermatan sulfates in the regulation of hepatocyte growth factor/scatter factor". The Journal of Biological Chemistry. 277 (2): 1040–6. doi:10.1074/jbc.M107506200. PMID 11689562. S2CID 29982976.
36. Lyon M, Deakin JA, Rahmoune H, Fernig DG, Nakamura T, Gallagher JT (Jan 1998). "Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulfate". J Biol Chem. 273 (1): 271–8. doi:10.1074/jbc.273.1.271. PMID 9417075. S2CID 39689713.
37. Sergeant N, Lyon M, Rudland PS, Fernig DG, Delehedde M (June 2000). "Stimulation of DNA synthesis and cell proliferation of human mammary myoepithelial-like cells by hepatocyte growth factor/scatter factor depends on heparan sulfate proteoglycans and sustained phosphorylation of mitogen-activated protein kinases p42/44". The Journal of Biological Chemistry. 275 (22): 17094–9. doi:10.1074/jbc.M000237200. PMID 10747885. S2CID 25507615.

Further reading

• Michalopoulos GK, Zarnegar R (1992). "Hepatocyte Growth Factor". Hepatology. 15 (1): 149–54. 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): L924-40. 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): 277–82. PMID 14626426.
• Kalluri R, Neilson EG (December 2003). "Epithelial-mesenchymal transition and its implications for fibrosis". The Journal of Clinical Investigation. 112 (12): 1776–84. doi:10.1172/JCI20530. PMC 297008. PMID 14679171.
• Hurle RA, Davies G, Parr C, Mason MD, Jenkins SA, Kynaston HG, Jiang WG (October 2005). "Hepatocyte growth factor/scatter factor and prostate cancer: a review". Histology and Histopathology. 20 (4): 1339–49. 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): 414–7. doi:10.1042/BST0340414. PMID 16709175. S2CID 31340761.
• Ejaz A, Epperly MW, Hou W, Greenberger JS, Rubin PJ (March 2019). "Adipose‐derived stem cell therapy ameliorates ionizing irradiation fibrosis (RIF) via hepatocyte growth factor mediated TGF‐β down regulation and recruitment of bone marrow cells". Stem Cells. 37 (6): 791–802. doi:10.1002/stem.3000. PMID 30861238.

External links

• Hepatocyte+growth+factor at the US National Library of Medicine Medical Subject Headings (MeSH)
• Hepatocyte growth factor on the Atlas of Genetics and Oncology
• UCSD Signaling Gateway Molecule Page on HGF
• Overview of all the structural information available in the PDB for UniProt: P14210 (Hepatocyte growth factor) at the PDBe-KB.