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
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]
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]
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]
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^ abBottaro 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. PMID1846706.
^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. PMID18649012. S2CID23419866.
^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. PMID21898720. S2CID26812780.
^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. PMID7555716.
^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. PMID10219907. S2CID9310133.
^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. PMID23218577.
^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. PMID21572126. S2CID22426278.
^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. PMID9886892. S2CID6615179.
^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. PMID8450646.
^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. PMID8045504. S2CID20021569.
^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. PMID25649658.
^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". Science of the Total Environment. 725: 138433. Bibcode:2020ScTEn.72538433H. doi:10.1016/j.scitotenv.2020.138433. PMID32302844.
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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