Pathway Map Details

Development_HGF signaling pathway



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HGF, COX-2 (PTGS2), PtdIns(4,5)P2, MEKK1 (MAP3K1), MKK7 (MAP2K7), IP3, MEK2(MAP2K2), SOS, STAT3, PtdIns(3,4,5)P3, AKT(PKB), GSK3 beta, EGR1, HGFA, 3.1.4.11, FasR(CD95), Syndecan-1, SNAIL1, CrkL, TCF7L2 (TCF4), PI3K reg class IA, DAG, PLC-gamma 1, Elk-1, JNK(MAPK8-10), c-Fos, C3G, GAB1, PLAU (UPA), c-Jun, CRK, RAP-1A, PDK (PDPK1), 2.7.1.137, PI3K cat class IA, Shc, Rac1, E-cadherin, ERK1/2, Beta-catenin, MEK4 (MAP2K4), H-Ras, DOCK2, GRB2, HGF receptor (Met), c-Raf-1, MEK1(MAP2K1)

Description:

HGF signaling

Hepatocyte growth factor/Scatter factor ( HGF ) is a multifunctional growth factor which induces cell dissociation, migration, protection from apoptosis, proliferation and differentiation [1]. Receptor Met proto-oncogene ( HGF receptor (Met) ) has tyrosine-kinase activity and predominantly expressed in the cells of epithelial or endothelial origin.

HGF is produced primarily by mesenchymal cells and secreted as an inactive zymogen, which is cleaved by a serine protease to initiate HGF receptor (Met) signaling. HGF -specific serine protease is HGF activator ( HGFA ) [2]. Syndecan-1 binds to HGF by its HS moieties and promotes signaling through HGF receptor (Met) [3]. Urokinase-type plasminogen activator ( PLAU) also cleavage HGF [4].

Upon binding ligands, tyrosine kinase receptors dimerize and autophosphorylate conservative residues in their cytoplasmic tail generating docking sites for intracellular signal transducers [5]. The multisubstrate docking site mediates binding of several adapter proteins such as Growth factor receptor-bound protein 2 ( GRB2), SHC transforming protein 1 (Shc), V-crk sarcoma virus CT10 oncogene homolog (avian)-like ( CrkL), GRB2-associated binding protein 1 ( GAB1), the regulatory subunit of Phosphatidylinositol-3-kinase ( PI3K reg class 1A ), Phospholipase C gamma 1 ( PLC-gamma1 ), Signal transducer and activator of transcription 3 ( STAT3 ), thereby activating different signal cascades [6].

HGF stimulates recruitment of Signal transducer and activator of transcription 3 ( STAT3 ) to the receptor, tyrosine phosphorylation, nuclear translocation and binding to the specific promoter element [7].

GAB1, a large scaffold adaptor protein, is phosphorylated in association with the activated HGF receptor (Met). GAB1 is responsible for HGF -induced scattering and branching morphogenesis of epithelial cells [5] GAB1 recruits several important substrates to activated HGF receptor (Met), for example PLC-gamma [1], [5], Shc, SHP-2, CrkL, GRB2 and PI3K. Thereby, GAB1 amplifes HGF receptor (Met) signaling [5]. PLC-gamma1 also can bind to HGF receptor (Met) directly (weak binding) [8].

Phosphorylated GAB1 binds CrkL. CrkL binds to Rap guanine nucleotide exchange factor 1 ( C3G) that activates GTPase Rap1 [9]. CrkL also binds Dedicator of cytokinesis 2 ( DOCK2), an exchange factor for Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) [10]. Thus, in response to HGF, HGF receptor (Met) activates both Rap1 and Rac1, involved in cell adhesion, spreading, dissociation, and migration [11] CrkL can signal through Rac1 to activate JNK-signaling pathway [12]. HGF mediates EMT via V-crk sarcoma virus CT10 oncogene homolog ( CRK ) and CrkL/ DOCK2 -mediated Rac1 activation [13], [14], [15]. HGF receptor (Met)- dependent activation of Snail homolog 2 ( SLUG ) is important to induce EMT and for cell survival during partial epithelial-to-mesenchymal transition (EMT) [16], [17].

GRB2 associates with son of sevenless homologes ( SOS ) and couples HGF receptor (Met) with v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-Ras )/ v-raf-1 murine leukemia viral oncogene homolog 1 ( c-Raf-1 )/ Mitogen-activated protein kinase kinases 1 and 2 ( MEK1 and MEK2 )/ Mitogen-activated protein kinases 3 and 1 ( ERK1/2 ) to the interaction with H-Ras (and thus to the downstream mitogen-activated protein kinase pathway) is mandatory for the consequential cell proliferation [1]. H-Ras is required for epithelial adhesion junction disassembly induced by HGF through activation of both PI3K and ERK1/2 [5]. HGF activates molecular pathways that lead to ERK1/2/ Early growth response 1 ( EGR1 )-dependent activation of snail homolog 1( SNAIL1 ) gene expression and downregulation of Cadherin 1 type 1 E-cadherin ( E-cadherin ) and EMT [18].

HGF participates in inhibition of anoikis. This pathway proceeds via activation of transcriptional factor AP-1 by ERK1/2 -dependent transcription of Cyclooxygenase-2 ( COX-2 (PTGS2) ) [19]. ERK1/2 -dependent activation of COX-2 is, probably, mediated by transcriptional factors of AP-1 group (V-fos FBJ murine osteosarcoma viral oncogene homolog ( c-Fos ) and Jun oncogene ( c-Jun )) [19], [20]. Activation of c-Fos transcription by ERK1/2 commonly performed via ELK1 member of ETS oncogene family ( Elk-1 ) [21]. Also, HGF in bronchial epithelium induces COX-2 expression in PI3K -dependent manner. This pathway is described below. ERK1/2 in this case participates in activation of Beta-catenin -dependent transcription [22].

PI3K activation proceeds via recruitment of its regulatory subunits. Active PI3K produces Phosphatidylinositol 3,4,5-triphosphate ( PtdIns(3,4,5)P3 ) involved in regulation of multiple cellular processes [23], [5]. AKT inhibits Glycogen synthase kinase 3 beta ( GSK3 beta ), this promotes Beta-catenin translocation to the nucleus. Beta-catenin via Transcription factor 7-like 2 ( TCF7L2 (TCF4) ) activates transcription of COX-2. ERK1/2 also participates in activation of Beta-catenin [22].

HGF can prevent apoptosis via direct binding and inhibition of FASR [24].

V-src sarcoma viral oncogene homolog ( c-Src ) activation is important for the HGF- mediated cell migration and cell transformation [11] c-Src induces phosphorylation and activation of Paxillin and Focal adhesion kinase ( FAK ) [5].

References:

  1. Comoglio PM
    Pathway specificity for Met signalling. Nature cell biology 2001 Jul;3(7):E161-2
  2. van Adelsberg J, Sehgal S, Kukes A, Brady C, Barasch J, Yang J, Huan Y
    Activation of hepatocyte growth factor (HGF) by endogenous HGF activator is required for metanephric kidney morphogenesis in vitro. The Journal of biological chemistry 2001 May 4;276(18):15099-106
  3. Derksen PW, Keehnen RM, Evers LM, van Oers MH, Spaargaren M, Pals ST
    Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. Blood 2002 Feb 15;99(4):1405-10
  4. Naldini L, Vigna E, Bardelli A, Follenzi A, Galimi F, Comoglio PM
    Biological activation of pro-HGF (hepatocyte growth factor) by urokinase is controlled by a stoichiometric reaction. The Journal of biological chemistry 1995 Jan 13;270(2):603-11
  5. Zhang YW, Vande Woude GF
    HGF/SF-met signaling in the control of branching morphogenesis and invasion. Journal of cellular biochemistry 2003 Feb 1;88(2):408-17
  6. Tulasne D, Paumelle R, Weidner KM, Vandenbunder B, Fafeur V
    The multisubstrate docking site of the MET receptor is dispensable for MET-mediated RAS signaling and cell scattering. Molecular biology of the cell 1999 Mar;10(3):551-65
  7. Boccaccio C, Ando M, Tamagnone L, Bardelli A, Michieli P, Battistini C, Comoglio PM
    Induction of epithelial tubules by growth factor HGF depends on the STAT pathway. Nature 1998 Jan 15;391(6664):285-8
  8. Ponzetto C, Bardelli A, Zhen Z, Maina F, dalla Zonca P, Giordano S, Graziani A, Panayotou G, Comoglio PM
    A multifunctional docking site mediates signaling and transformation by the hepatocyte growth factor/scatter factor receptor family. Cell 1994 Apr 22;77(2):261-71
  9. Sakkab D, Lewitzky M, Posern G, Schaeper U, Sachs M, Birchmeier W, Feller SM
    Signaling of hepatocyte growth factor/scatter factor (HGF) to the small GTPase Rap1 via the large docking protein Gab1 and the adapter protein CRKL. The Journal of biological chemistry 2000 Apr 14;275(15):10772-8
  10. Cote JF, Vuori K
    Identification of an evolutionarily conserved superfamily of DOCK180-related proteins with guanine nucleotide exchange activity. Journal of cell science 2002 Dec 15;115(Pt 24):4901-13
  11. Furge KA, Zhang YW, Vande Woude GF
    Met receptor tyrosine kinase: enhanced signaling through adapter proteins. Oncogene 2000 Nov 20;19(49):5582-9
  12. Garcia-Guzman M, Dolfi F, Zeh K, Vuori K
    Met-induced JNK activation is mediated by the adapter protein Crk and correlates with the Gab1 - Crk signaling complex formation. Oncogene 1999 Dec 16;18(54):7775-86
  13. Nishihara H, Maeda M, Oda A, Tsuda M, Sawa H, Nagashima K, Tanaka S
    DOCK2 associates with CrkL and regulates Rac1 in human leukemia cell lines. Blood 2002 Dec 1;100(12):3968-74
  14. Lamorte L, Park M
    ARF1 and ARF6 are dispensable for Crk-dependent epithelial-mesenchymal-like transitions. Anticancer research 2003 May-Jun;23(3A):2085-92
  15. Lamorte L, Royal I, Naujokas M, Park M
    Crk adapter proteins promote an epithelial-mesenchymal-like transition and are required for HGF-mediated cell spreading and breakdown of epithelial adherens junctions. Molecular biology of the cell 2002 May;13(5):1449-61
  16. Savagner P, Yamada KM, Thiery JP
    The zinc-finger protein slug causes desmosome dissociation, an initial and necessary step for growth factor-induced epithelial-mesenchymal transition. The Journal of cell biology 1997 Jun 16;137(6):1403-19
  17. Leroy P, Mostov KE
    Slug is required for cell survival during partial epithelial-mesenchymal transition of HGF-induced tubulogenesis. Molecular biology of the cell 2007 May;18(5):1943-52
  18. Grotegut S, von Schweinitz D, Christofori G, Lehembre F
    Hepatocyte growth factor induces cell scattering through MAPK/Egr-1-mediated upregulation of Snail. The EMBO journal 2006 Aug 9;25(15):3534-45
  19. Zeng Q, McCauley LK, Wang CY
    Hepatocyte growth factor inhibits anoikis by induction of activator protein 1-dependent cyclooxygenase-2. Implication in head and neck squamous cell carcinoma progression. The Journal of biological chemistry 2002 Dec 20;277(51):50137-42
  20. Siegfried JM, Gubish CT, Rothstein ME, Queiroz de Oliveira PE, Stabile LP
    Signaling pathways involved in cyclooxygenase-2 induction by hepatocyte growth factor in non small-cell lung cancer. Molecular pharmacology 2007 Sep;72(3):769-79
  21. Galetic I, Maira SM, Andjelkovic M, Hemmings BA
    Negative regulation of ERK and Elk by protein kinase B modulates c-Fos transcription. The Journal of biological chemistry 2003 Feb 14;278(7):4416-23
  22. Lee YH, Suzuki YJ, Griffin AJ, Day RM
    Hepatocyte growth factor regulates cyclooxygenase-2 expression via beta-catenin, Akt, and p42/p44 MAPK in human bronchial epithelial cells. American journal of physiology. Lung cellular and molecular physiology 2008 Apr;294(4):L778-86
  23. Katso R, Okkenhaug K, Ahmadi K, White S, Timms J, Waterfield MD
    Cellular function of phosphoinositide 3-kinases: implications for development, homeostasis, and cancer. Annual review of cell and developmental biology 2001;17:615-75
  24. Wang X, DeFrances MC, Dai Y, Pediaditakis P, Johnson C, Bell A, Michalopoulos GK, Zarnegar R
    A mechanism of cell survival: sequestration of Fas by the HGF receptor Met. Molecular cell 2002 Feb;9(2):411-21