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][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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.{{
cite book}}: CS1 maint: multiple names: authors list (
link)
^
abBottaro 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.
PMID1846706.
^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.
PMID18649012.
S2CID23419866.
^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.
PMID21898720.
S2CID26812780.
^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.
doi:
10.1242/dev.121.9.2897.
PMID7555716.
^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.
PMID10219907.
S2CID9310133.
^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.
PMID23218577.
^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.
PMID21572126.
S2CID22426278.
^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.
PMID9886892.
S2CID6615179.
^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.
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): 417–24.
doi:
10.1002/hep.1840200223.
PMID8045504.
S2CID20021569.
^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.
PMID25649658.
^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.
PMID25455861.
S2CID41360989.
^Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". Exs. 65: 131–65.
PMID8380735.
^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.
PMID7553606.
^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.
PMID8930021.
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.
PMID1838014.
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.
PMID11943656.
S2CID22175256.
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.
PMID12482615.
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.
PMID14626426.
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.
PMID16136515.
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.
PMID16709175.
S2CID31340761.
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
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][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]
^"Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^"Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
^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.{{
cite book}}: CS1 maint: multiple names: authors list (
link)
^
abBottaro 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.
PMID1846706.
^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.
PMID18649012.
S2CID23419866.
^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.
PMID21898720.
S2CID26812780.
^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.
doi:
10.1242/dev.121.9.2897.
PMID7555716.
^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.
PMID10219907.
S2CID9310133.
^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.
PMID23218577.
^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.
PMID21572126.
S2CID22426278.
^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.
PMID9886892.
S2CID6615179.
^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.
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): 417–24.
doi:
10.1002/hep.1840200223.
PMID8045504.
S2CID20021569.
^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.
PMID25649658.
^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.
PMID25455861.
S2CID41360989.
^Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". Exs. 65: 131–65.
PMID8380735.
^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.
PMID7553606.
^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.
PMID8930021.
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.
PMID1838014.
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.
PMID11943656.
S2CID22175256.
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.
PMID12482615.
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.
PMID14626426.
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.
PMID16136515.
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.
PMID16709175.
S2CID31340761.
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