Hepatocyte Growth Factor - Wikipedia

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• 1 Function
• 2 Structure
• 3 Clinical significance Toggle Clinical significance subsection
  • 3.1 Circulating plasma levels
• 4 Pharmacokinetics
• 5 Modulators
• 6 Interactions
• 7 See also
• 8 References
• 9 Further reading
• 10 External links

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Appearance move to sidebar hide From Wikipedia, the free encyclopedia Mammalian protein found in Homo sapiens

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; OMA:HGF - orthologs
Gene location (Human) Chr. Chromosome 7 (human)[1] Band 7q21.11 Start 81,699,010 bp[1] End 81,770,438 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5 A3|5 7.07 cM Start 16,758,493 bp[2] End 16,825,150 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in placenta stromal cell of endometrium visceral pleura buccal mucosa cell monocyte pancreatic epithelial cell gallbladder Epithelium of choroid plexus liver right coronary artery Top expressed in lumbar spinal ganglion granulocyte urethra stria vascularis genital tubercle embryo primitive endoderm pineal gland abdominal wall right lung lobe More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding identical protein binding chemoattractant activity protein heterodimerization activity growth factor activity serine-type endopeptidase activity protein tyrosine kinase activity phosphatidylinositol-4,5-bisphosphate 3-kinase activity Cellular component membrane extracellular region platelet alpha granule lumen extracellular space 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 myoblast proliferation negative regulation of extrinsic apoptotic signaling pathway via death domain receptors animal organ regeneration cell morphogenesis positive regulation of cell population proliferation hyaluronan metabolic process positive regulation of DNA biosynthetic process negative regulation of peptidyl-serine phosphorylation epithelial to mesenchymal transition positive regulation of peptidyl-tyrosine phosphorylation cell chemotaxis liver development positive regulation of phosphatidylinositol 3-kinase signaling regulation of p38MAPK cascade cell population proliferation negative regulation of autophagy hepatocyte growth factor receptor signaling pathway negative regulation of inflammatory response positive regulation of transcription by RNA polymerase II regulation of tau-protein kinase activity proteolysis positive chemotaxis MAPK cascade peptidyl-tyrosine phosphorylation phosphatidylinositol phosphate biosynthetic process mitotic cell cycle regulation of signaling 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_000601NM_001010931NM_001010932NM_001010933NM_001010934 NM_010427NM_001289458NM_001289459NM_001289460NM_001289461 RefSeq (protein) NP_000592NP_001010931NP_001010932NP_001010933NP_001010934 NP_001276387NP_001276388NP_001276389NP_001276390NP_034557 Location (UCSC) Chr 7: 81.7 – 81.77 Mb Chr 5: 16.76 – 16.83 Mb PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

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]

Function

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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]

Structure

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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]

Clinical significance

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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

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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]

Pharmacokinetics

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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]

Modulators

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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][31] It is a strong inducer of neurogenesis and is being studied for the potential treatment of Alzheimer's disease and Parkinson's disease.[32][33]

Interactions

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Hepatocyte growth factor has been shown to interact with the protein product of the c-Met oncogene, identified as the HGF receptor (HGFR).[6][34][35] 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.[36][37] Hepatocyte growth factor interacts with the sulfated glycosaminoglycans heparan sulfate and dermatan sulfate.[38][39] 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.[38][40]

See also

[edit]

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

References

[edit]

1. ^ a b c GRCh38: Ensembl release 89: ENSG00000019991 – Ensembl, May 2017
2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000028864 – Ensembl, May 2017
3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. ^ 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.
6. ^ a b Bottaro DP, Rubin JS, Faletto DL, Chan AM, Kmiecik TE, Vande Woude GF, et al. (February 1991). "Identification of the hepatocyte growth factor receptor as the c-met proto-oncogene product". Science. 251 (4995): 802–804. Bibcode:1991Sci...251..802B. doi:10.1126/science.1846706. PMID 1846706.
7. ^ 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): 1052–1061. doi:10.1016/0270-9139(93)90122-4. PMID 8514254.
8. ^ Custo S, Baron B, Felice A, Seria E (5 July 2022). "A comparative profile of total protein and six angiogenically-active growth factors in three platelet products". GMS Interdisciplinary Plastic and Reconstructive Surgery DGPW. 11 (Doc06): Doc06. doi:10.3205/iprs000167. PMC 9284722. PMID 35909816.
9. ^ a b "Entrez Gene: HGF hepatocyte growth factor (hepapoietin A; scatter factor)".
10. ^ 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.
11. ^ 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.
12. ^ Komarowska I, Coe D, Wang G, Haas R, Mauro C, Kishore M, et al. (June 2015). "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): 1087–1099. doi:10.1016/j.immuni.2015.05.014. PMC 4510150. PMID 26070483.
13. ^ Chang HK, Kim PH, Cho HM, Yum SY, Choi YJ, Son Y, et al. (September 2016). "Inducible HGF-secreting Human Umbilical Cord Blood-derived MSCs Produced via TALEN-mediated Genome Editing Promoted Angiogenesis". Molecular Therapy. 24 (9): 1644–1654. doi:10.1038/mt.2016.120. PMC 5113099. PMID 27434585.
14. ^ Chow A, Her Z, Ong EK, Chen JM, Dimatatac F, Kwek DJ, et al. (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): 149–157. doi:10.1093/infdis/jiq042. PMC 3071069. PMID 21288813.
15. ^ Zhong A, Wang G, Yang J, Xu Q, Yuan Q, Yang Y, et al. (July 2014). "Stromal-epithelial cell interactions and alteration of branching morphogenesis in macromastic mammary glands". Journal of Cellular and Molecular Medicine. 18 (7): 1257–1266. doi:10.1111/jcmm.12275. PMC 4124011. PMID 24720804.
16. ^ 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.
17. ^ 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.
18. ^ 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.
19. ^ 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): 715–717. doi:10.1158/1055-9965.EPI-04-0340. PMID 15767355. S2CID 3089594.
20. ^ El-Attar HA, Sheta MI (2011). "Hepatocyte growth factor profile with breast cancer". Indian Journal of Pathology & Microbiology. 54 (3): 509–513. doi:10.4103/0377-4929.85083. PMID 21934211.
21. ^ Dally J, Khan JS, Voisey A, Charalambous C, John HL, Woods EL, et al. (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.
22. ^ 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.
23. ^ 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.
24. ^ 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.
25. ^ 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.
26. ^ 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): 848–859. doi:10.1053/jhep.2001.23438. PMC 1821076. PMID 11283849.
27. ^ 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.
28. ^ 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.
29. ^ Yu Y, Yao AH, Chen N, Pu LY, Fan Y, Lv L, et al. (July 2007). "Mesenchymal stem cells over-expressing hepatocyte growth factor improve small-for-size liver grafts regeneration". Molecular Therapy. 15 (7): 1382–1389. doi:10.1038/sj.mt.6300202. PMID 17519892.
30. ^ Wright JW, Harding JW (January 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.
31. ^ Hu B, Yin N, Yang R, Liang S, Liang S, Faiola F (July 2020). "Silver nanoparticles (AgNPs) and AgNO3 perturb the specification of human hepatocyte-like cells and cardiomyocytes". The Science of the Total Environment. 725 138433. Bibcode:2020ScTEn.72538433H. doi:10.1016/j.scitotenv.2020.138433. PMID 32302844.
32. ^ 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.
33. ^ 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.
34. ^ Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". Exs. 65: 131–165. PMID 8380735.
35. ^ Naldini L, Weidner KM, Vigna E, Gaudino G, Bardelli A, Ponzetto C, et al. (October 1991). "Scatter factor and hepatocyte growth factor are indistinguishable ligands for the MET receptor". The EMBO Journal. 10 (10): 2867–2878. doi:10.1002/j.1460-2075.1991.tb07836.x. PMC 452997. PMID 1655405.
36. ^ 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.
37. ^ 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.
38. ^ a b 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): 1040–1046. doi:10.1074/jbc.M107506200. PMID 11689562. S2CID 29982976.
39. ^ Lyon M, Deakin JA, Rahmoune H, Fernig DG, Nakamura T, Gallagher JT (January 1998). "Hepatocyte growth factor/scatter factor binds with high affinity to dermatan sulfate". The Journal of Biological Chemistry. 273 (1): 271–278. doi:10.1074/jbc.273.1.271. PMID 9417075. S2CID 39689713.
40. ^ 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): 17094–17099. doi:10.1074/jbc.M000237200. PMID 10747885. S2CID 25507615.

Further reading

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• 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.

External links

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• Hepatocyte+growth+factor at the U.S. 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.

v t e PDB gallery

1bht: NK1 FRAGMENT OF HUMAN HEPATOCYTE GROWTH FACTOR 1gmn: CRYSTAL STRUCTURES OF NK1-HEPARIN COMPLEXES REVEAL THE BASIS FOR NK1 ACTIVITY AND ENABLE ENGINEERING OF POTENT AGONISTS OF THE MET RECEPTOR 1gmo: CRYSTAL STRUCTURES OF NK1-HEPARIN COMPLEXES REVEAL THE BASIS FOR NK1 ACTIVITY AND ENABLE ENGINEERING OF POTENT AGONISTS OF THE MET RECEPTOR 1gp9: A NEW CRYSTAL FORM OF THE NK1 SPLICE VARIANT OF HGF/SF DEMONSTRATES EXTENSIVE HINGE MOVEMENT AND SUGGESTS THAT THE NK1 DIMER ORIGINATES BY DOMAIN SWAPPING 1nk1: NK1 FRAGMENT OF HUMAN HEPATOCYTE GROWTH FACTOR/SCATTER FACTOR (HGF/SF) AT 2.5 ANGSTROM RESOLUTION 1shy: The Crystal Structure of HGF beta-chain in Complex with the Sema Domain of the Met Receptor. 1si5: Protease-like domain from 2-chain hepatocyte growth factor 2hgf: HAIRPIN LOOP CONTAINING DOMAIN OF HEPATOCYTE GROWTH FACTOR, NMR, MINIMIZED AVERAGE STRUCTURE

v t e Intercellular signaling peptides and proteins / ligands
Growth factors	Epidermal growth factor Fibroblast growth factor Nerve growth factor Platelet-derived growth factor Transforming growth factor beta superfamily Vascular endothelial growth factor
Ephrin	EFNA1 EFNA2 EFNA3 EFNA4 EFNA5 EFNB1 EFNB2 EFNB3
Other	Adipokine Agouti signaling protein Agouti-related protein Angiogenic protein CCN intercellular signaling protein Cysteine-rich protein 61 Connective tissue growth factor Nephroblastoma overexpressed protein Cytokine Endothelin EDN1 EDN2 EDN3 Hedgehog protein Interferon Kinin Parathyroid hormone-related protein Semaphorin Somatomedin Tolloid-like metalloproteinase Tumor necrosis factor Wnt protein
see also extracellular ligand disorders

v t e Growth factors
Fibroblast	FGF receptor ligands: FGF1/FGF2/FGF5 FGF3/FGF4/FGF6 KGF FGF7/FGF10/FGF22 FGF8/FGF17/FGF18 FGF9/FGF16/FGF20 FGF homologous factors: FGF11(FHF3) FGF12(FHF1) FGF13(FHF2) FGF14(FHF4) hormone-like: FGF15/19 FGF15 FGF19 FGF21 FGF23
EGF-like domain	TGFα EGF HB-EGF
TGFβ pathway	TGFβ TGFβ1 TGFβ2 TGFβ3
Insulin/IGF/Relaxin family	Insulin and Insulin-like growth factor IGF1 IGF2 Relaxin family peptide hormones INSL3 INSL4 INSL5 INSL6 Relaxin 1 2 3
Platelet-derived	PDGFA PDGFB PDGFC PDGFD
Vascular endothelial	VEGF-A VEGF-B VEGF-C VEGF-D PGF
Other	Nerve Hepatocyte

v t e Growth factor receptor modulators
Angiopoietin	Agonists: Angiopoietin 1 Angiopoietin 4 Antagonists: Angiopoietin 2 Angiopoietin 3 Kinase inhibitors: Altiratinib CE-245677 Rebastinib Antibodies: Evinacumab (against angiopoietin 3) Nesvacumab (against angiopoietin 2)
CNTF	Agonists: Axokine CNTF Dapiclermin
EGF (ErbB)	EGF(ErbB1/HER1) Agonists: Amphiregulin Betacellulin EGF (urogastrone) Epigen Epiregulin Heparin-binding EGF-like growth factor (HB-EGF) Murodermin Nepidermin Transforming growth factor alpha (TGFα) Kinase inhibitors: Afatinib Agerafenib Brigatinib Canertinib Dacomitinib Erlotinib Gefitinib Grandinin Icotinib Lapatinib Neratinib Osimertinib Vandetanib WHI-P 154 Antibodies: Cetuximab Depatuxizumab Depatuxizumab mafodotin Futuximab Imgatuzumab Matuzumab Necitumumab Nimotuzumab Panitumumab Zalutumumab ErbB2/HER2 Agonists: Unknown/none Antibodies: Ertumaxomab Pertuzumab Trastuzumab Trastuzumab deruxtecan Trastuzumab duocarmazine Trastuzumab emtansine Kinase inhibitors: Afatinib Lapatinib Mubritinib Neratinib Tucatinib ErbB3/HER3 Agonists: Neuregulins (heregulins) (1, 2, 6 (neuroglycan C)) Antibodies: Duligotumab Patritumab Seribantumab ErbB4/HER4 Agonists: Betacellulin Epigen Heparin-binding EGF-like growth factor (HB-EGF) Neuregulins (heregulins) (1, 2, 3, 4, 5 (tomoregulin, TMEFF))
FGF	FGFR1 Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 8, 10 (KGF2), 20) Repifermin Selpercatinib Trafermin Velafermin FGFR2 Agonists: Ersofermin FGF (1, 2 (bFGF), 3, 4, 5, 6, 7 (KGF), 8, 9, 10 (KGF2), 17, 18, 22) Palifermin Repifermin Selpercatinib Sprifermin Trafermin Antibodies: Aprutumab Aprutumab ixadotin Kinase inhibitors: Infigratinib FGFR3 Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 8, 9, 18, 23) Selpercatinib Sprifermin Trafermin Antibodies: Burosumab (against FGF23) FGFR4 Agonists: Ersofermin FGF (1, 2 (bFGF), 4, 6, 8, 9, 19) Trafermin Unsorted Agonists: FGF15/19
HGF (c-Met)	Agonists: Fosgonimeton Hepatocyte growth factor Potentiators: Dihexa (PNB-0408) Kinase inhibitors: Altiratinib AM7 AMG-458 Amuvatinib BMS-777607 Cabozantinib Capmatinib Crizotinib Foretinib Golvatinib INCB28060 JNJ-38877605 K252a MK-2461 PF-04217903 PF-2341066 PHA-665752 SU-11274 Tivantinib Volitinib Antibodies: Emibetuzumab Ficlatuzumab Flanvotumab Onartuzumab Rilotumumab Telisotuzumab Telisotuzumab vedotin
IGF	IGF-1 Agonists: des(1-3)IGF-1 Insulin-like growth factor-1 (somatomedin C) IGF-1 LR3 Insulin-like growth factor-2 (somatomedin A) Insulin Mecasermin Mecasermin rinfabate Kinase inhibitors: BMS-754807 Linsitinib NVP-ADW742 NVP-AEW541 OSl-906 Antibodies: AVE-1642 Cixutumumab Dalotuzumab Figitumumab Ganitumab Robatumumab R1507 Teprotumumab Xentuzumab (against IGF-1 and IGF-2) IGF-2 Agonists: Insulin-like growth factor-2 (somatomedin A) Antibodies: Dusigitumab Xentuzumab (against IGF-1 and IGF-2) Others Binding proteins: IGFBP (1, 2, 3, 4, 5, 6, 7) Cleavage products/derivatives with unknown target: Glypromate (GPE, (1-3)IGF-1) Trofinetide
LNGF (p75NTR)	Agonists: BDNF BNN-20 BNN-27 Cenegermin DHEA DHEA-S NGF NT-3 NT-4 Antagonists: ALE-0540 Dexamethasone EVT-901 (SAR-127963) Testosterone Antibodies: Against NGF: ABT-110 (PG110) ASP-6294 Fasinumab Frunevetmab Fulranumab MEDI-578 Ranevetmab Tanezumab Aptamers: Against NGF: RBM-004 Decoy receptors: LEVI-04 (p75NTR-Fc)
PDGF	Agonists: Becaplermin Platelet-derived growth factor (A, B, C, D) Kinase inhibitors: Agerafenib Avapritinib Axitinib Crenolanib Imatinib Lenvatinib Masitinib Motesanib Nintedanib Pazopanib Radotinib Quizartinib Ripretinib Sunitinib Sorafenib Toceranib Antibodies: Olaratumab Ramucirumab Tovetumab
RET (GFL)	GFRα1 Agonists: Glial cell line-derived neurotrophic factor (GDNF) Liatermin Kinase inhibitors: Vandetanib GFRα2 Agonists: Neurturin (NRTN) Kinase inhibitors: Vandetanib GFRα3 Agonists: Artemin (ARTN) Kinase inhibitors: Vandetanib GFRα4 Agonists: Persephin (PSPN) Kinase inhibitors: Vandetanib Unsorted Kinase inhibitors: Agerafenib
SCF (c-Kit)	Agonists: Ancestim Stem cell factor Kinase inhibitors: Agerafenib Axitinib Dasatinib Imatinib Masitinib Nilotinib Pazopanib Quizartinib Sorafenib Sunitinib Toceranib
TGFβ	See here instead.
Trk	TrkA Agonists: Amitriptyline BNN-20 BNN-27 Cenegermin DHEA DHEA-S Gambogic amide NGF Tavilermide Antagonists: ALE-0540 Dexamethasone FX007 Testosterone Negative allosteric modulators: VM-902A Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib Milciclib ONO-4474 ONO-5390556 PLX-7486 Rebastinib SNA-120 (pegylated K252a)) Antibodies: Against TrkA: GBR-900; Against NGF: ABT-110 (PG110) ASP-6294 Fasinumab Frunevetmab Fulranumab MEDI-578 Ranevetmab Tanezumab Aptamers: Against NGF: RBM-004 Decoy receptors: ReN-1820 (TrkAd5) TrkB Agonists: 3,7-DHF 3,7,8,2'-THF 4'-DMA-7,8-DHF 7,3'-DHF 7,8-DHF 7,8,2'-THF 7,8,3'-THF Amitriptyline BDNF BNN-20 Deoxygedunin Deprenyl Diosmetin DMAQ-B1 HIOC LM22A-4 N-Acetylserotonin NT-3 NT-4 Norwogonin (5,7,8-THF) R7 R13 TDP6 Antagonists: ANA-12 Cyclotraxin B Gossypetin (3,5,7,8,3',4'-HHF) Ligands: DHEA Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib ONO-4474 ONO-5390556 PLX-7486 TrkC Agonists: BNN-20 DHEA NT-3 Kinase inhibitors: Altiratinib AZD-6918 CE-245677 CH-7057288 DS-6051 Entrectinib GZ-389988 K252a Larotrectinib Lestaurtinib ONO-4474 ONO-5390556 PLX-7486
VEGF	Agonists: Placental growth factor (PGF) Ripretinib Telbermin VEGF (A, B, C, D (FIGF)) Allosteric modulators: Cyclotraxin B Kinase inhibitors: Agerafenib Altiratinib Axitinib Cabozantinib Cediranib Fruquintinib Lapatinib Lenvatinib Motesanib Nintedanib Pazopanib Pegaptanib Rebastinib Regorafenib Semaxanib Sorafenib Sunitinib Toceranib Tivozanib Vandetanib WHI-P 154 Antibodies: Alacizumab pegol Bevacizumab Icrucumab Ramucirumab Ranibizumab Decoy receptors: Aflibercept
Others	Additional growth factors: Adrenomedullin Colony-stimulating factors (see here instead) Connective tissue growth factor (CTGF) Ephrins (A1, A2, A3, A4, A5, B1, B2, B3) Erythropoietin (see here instead) Glucose-6-phosphate isomerase (GPI; PGI, PHI, AMF) Glia maturation factor (GMF) Hepatoma-derived growth factor (HDGF) Interleukins/T-cell growth factors (see here instead) Leukemia inhibitory factor (LIF) Macrophage-stimulating protein (MSP; HLP, HGFLP) Midkine (NEGF2) Migration-stimulating factor (MSF; PRG4) Oncomodulin Pituitary adenylate cyclase-activating peptide (PACAP) Pleiotrophin Renalase Thrombopoietin (see here instead) Wnt signaling proteins Additional growth factor receptor modulators: Cerebrolysin (neurotrophin mixture)

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