Factor de crecemento de hepatocitos
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| PDB 1bht | |
Factor de crecemento de hepatocitos
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| Identificadores | |
| Símbolo | HGF |
| Símbolos alt. | DFNB39, F-TCF, HGFB, HPTA, SF, hepatocyte growth factor |
| Entrez | 3082 |
| OMIM | |
| RefSeq | NP_000592 |
| UniProt | P14210 |
| Outros datos | |
| Locus | Cr. 7 7q21.11:(81.7 – 81.77 Mb) |
O factor de crecemento de hepatocitos (HGF) (ou factor de dispersión, en inglés scatter factor ou SF) é un factor de crecemento celular parácrino, de motilidade e morfoxénico. É segregado polas células mesenquimais e ten como diana e actúa principalmente sobre células epiteliais e endoteliais, pero tamén actúa sobre as células proxenitoras hematopoéticas e células T. Ten un importante papel no desenvolvemento de órganos embrionarios, especificamente na mioxénese, na rexeneración de órganos adultos e na curación de feridas.[1]
Función
[editar | editar a fonte]O factor de crecemento do hepatocito regula o crecemento celular, a motilidade celular e a morfoxénese ao activar a fervenza de sinalización da tirosina quinase despois de unirse ao receptor protooncoxénico c-Met.[2][3] O HGR é segregado polas células mesenquimais e actúa como unha citocina multifuncional en células de orixe principalmente epitelial. A súa capacidade de estimular a mitoxénese, motilidade celular e invasión da matriz dálle un papel central na anxioxénese, tumoroxénese e rexeneración de tecidos.[4]
Estrutura
[editar | editar a fonte]Segrégase en forma dun só polipéptido inactivo e despois é clivado por serina proteases dando unha cadea alfa de 69 kDa e outra beta de 34 kDa. Unha ponte disulfuro entre as cadeas alfa e beta úneas dando lugar ao produto activo heterodimérico. A proteína pertence á subfamilia do plasminóxeno de peptidases S1, pero non ten actividade detectable de protease.[4]
Importancia clínica
[editar | editar a fonte]A terapia de ADN de plásmido de HGF humano de cardiomiocitos está sendo examinada como posible tratamento da enfermidade da arteria coronaria e como traramento para os danos ocorridos no corazón despois dun infarto de miocardio.[5][6] Ademais dos efectos ben caracterizados do HGF sobre as células epitaliais, endoteliais e proxenitoras hematopoéticas, o HGF tamén regula a quimiotaxe de células T no tecido cardíaco. A unión do HGF o c-Met, expresado en células T, causa a regulación á alza de c-Met, CXCR3 e CCR4, que á súa vez lles dá a capacidade de migrar ao tecido cardíaco.[7] O HGF tamén promociona a anxioxénese nas lesións isquémicas.[8] O HGF pode xogar un papel como indicador de prognóstico para a artralxia inducida polo virus Chikungunya. Os niveis altos de HGF correlaciónanse con altas taxas de recuperación.[9]
A expresión excesiva local de HGF nas mamas foi implicada na macromastia.[10] O HGFestá tamén implicado de forma importante no desenvolvemento normal da glándula mamaria.[11][12]
O HGF foi implicado en diversos cancros, como o de pulmón, páncreas, tiroide, colon e mama.[13][14][15]
O incremento da expresión de HGF foi asociada coas capacidades de mellora e non formación de cicatriz na curación de feridas de fibroblastos illados do tecido da mucosa oral.[16]
Niveis de plasma circulantes
[editar | editar a fonte]O plasma de pacientes con insuficiencia cardíaca avanzada presenta niveis incrementados de HGF, o cal se correlaciona cun prognóstico negativo e un alto risco de mortalidade.[17][18] O HGF circulante foi tamén identificado como marcador de prognóstico que indica gravidade en pacientes que padecen hipertensión.[19][19] O HGF circulante tamén se suxeriu como posible biomarcador precoz da fase aguda da inflamación intestinal.[20]
Farmacocinética
[editar | editar a fonte]O HGF exóxeno administrado por inxección intravenosa é eliminado rapidamente da circulación polo fígado, e ten unha vida media de aproximadamente 4 minutos.[21][22][23][24]
Moduladores
[editar | editar a fonte]Dihexa é unha pequena molécula oralmente activa e penetrante centralmente que se une directamente ao HGF e potencia a súa capacidade de activar o seu receptor, c-Met.[25] É un forte indutor da neuroxénese e está sendo estudada para a súa posible aplicación no tratamento da enfermidade de Alzheimer e a de Parkinson.[26][27]
Interaccións
[editar | editar a fonte]O factor de crecemento de hepatocitos presenta interaccións co produto proteico do oncoxene c-Met, identificado como receptor de HGF (HGFR).[2][28][29] Tanto a sobreexpresión da proteína do receptor Met/HGFR coma a activación autócrina de Met/HGFR pola expresión simultánea do ligando factor de crecemento de hepatocitos foron implicadas na oncoxénese.[30][31] O factor de crecemento de hepatocitos interacciona cos glicosaminoglicanos sufatados heparán sulfato e dermatán sulfato.[32][33] A interacción co heparán sulfato permite que o factor de crecemento de hepatocitos forme un complexo con c-Met que pode transducir sinais intracelulares que orixinarán a división celular e a migración celular.[32][34]
Notas
[editar | editar a fonte]- ↑ Gallagher, J.T., Lyon, M. (2000). "Molecular structure of Heparan Sulfate and interactions with growth factors and morphogens". En Iozzo, M, V. Proteoglycans: structure, biology and molecular interactions. Marcel Dekker Inc. New York, New York. pp. 27–59.
- ↑ 2,0 2,1 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. PMID 1846706. doi:10.1126/science.1846706.
- ↑ 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. PMID 8514254. doi:10.1016/0270-9139(93)90122-4.
- ↑ 4,0 4,1 "Entrez Gene: HGF hepatocyte growth factor (hepapoietin A; scatter factor)".
- ↑ 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. PMID 18649012. doi:10.1007/s11033-008-9315-3.
- ↑ 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. PMID 21898720. doi:10.1002/jgm.1603.
- ↑ 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. PMC 4510150. PMID 26070483. doi:10.1016/j.immuni.2015.05.014.
- ↑ 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. PMC 5113099. PMID 27434585. doi:10.1038/mt.2016.120.
- ↑ 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. PMC 3071069. PMID 21288813. doi:10.1093/infdis/jiq042.
- ↑ 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. PMC 4124011. PMID 24720804. doi:10.1111/jcmm.12275.
- ↑ 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.
- ↑ 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. PMID 10219907.
- ↑ 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.
- ↑ 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. PMID 15767355. doi:10.1158/1055-9965.EPI-04-0340.
- ↑ El-Attar HA, Sheta MI (2011). "Hepatocyte growth factor profile with breast cancer". Indian Journal of Pathology & Microbiology 54 (3): 509–13. PMID 21934211. doi:10.4103/0377-4929.85083.
- ↑ 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). PMC 5618492. PMID 28837064. doi:10.3390/ijms18091843.
- ↑ 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. PMID 23218577. doi:10.1016/j.ijcard.2012.11.052.
- ↑ 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. PMID 21572126. doi:10.1136/hrt.2010.220228.
- ↑ 19,0 19,1 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. PMID 9886892. doi:10.1291/hypres.22.161.
- ↑ 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. PMID 25174881. doi:10.1016/j.cyto.2014.07.255.
- ↑ 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. PMC 1821076. PMID 11283849. doi:10.1053/jhep.2001.23438.
- ↑ 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.
- ↑ 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. PMID 8045504. doi:10.1002/hep.1840200223.
- ↑ 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. PMID 17519892. doi:10.1038/sj.mt.6300202.
- ↑ 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. PMC 4201273. PMID 25187433. doi:10.1124/jpet.114.218735.
- ↑ 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. PMID 25649658. doi:10.3233/JAD-142814.
- ↑ 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. PMID 25455861. doi:10.1016/j.pneurobio.2014.11.004.
- ↑ Comoglio PM (1993). "Structure, biosynthesis and biochemical properties of the HGF receptor in normal and malignant cells". Exs 65: 131–65. PMID 8380735.
- ↑ 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. PMC 452997. PMID 1655405.
- ↑ 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. PMID 7553606. doi:10.1016/0304-3835(95)03915-j.
- ↑ 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. PMID 8930021. doi:10.3109/08977199509028968.
- ↑ 32,0 32,1 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. PMID 11689562. doi:10.1074/jbc.M107506200.
- ↑ 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. PMID 9417075. doi:10.1074/jbc.273.1.271.
- ↑ 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. PMID 10747885. doi:10.1074/jbc.M000237200.
Véxase tamén
[editar | editar a fonte]Outros artigos
[editar | editar a fonte]- Factor de crecemento epidérmico
- Factor de crecemento similar á insulina 1
- Transición epitelial-mesenquimal
Bibliografía
[editar | editar a fonte]- Michalopoulos GK, Zarnegar R (1992). "Hepatocyte Growth Factor". Hepatology 15 (1): 149–54. doi:10.1002/hep.1840150125.
- Nakamura T (1992). "Structure and function of hepatocyte growth factor". Progress in Growth Factor Research 3 (1): 67–85. PMID 1838014. doi:10.1016/0955-2235(91)90014-U.
- 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. PMID 11943656. doi:10.1152/ajplung.00439.2001.
- 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. PMID 12482615. doi:10.1016/S0009-8981(02)00302-9.
- 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. PMC 297008. PMID 14679171. doi:10.1172/JCI20530.
- 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. PMID 16136515. doi:10.14670/HH-20.1339.
- 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. PMID 16709175. doi:10.1042/BST0340414.
Ligazóns externas
[editar | editar a fonte]- Hepatocyte growth factor Medical Subject Headings (MeSH) na Biblioteca Nacional de Medicina dos EUA.
- Hepatocyte growth factor en Atlas of Genetics and Oncology
- Páxina da UCSD Signaling Gateway Molecule en HGF
