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, 18.104.22.168, 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), 22.214.171.124, 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)
Hepatocyte growth factor/Scatter factor ( HGF ) is a multifunctional growth factor which induces cell dissociation, migration, protection from apoptosis, proliferation and differentiation . 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 ) . Syndecan-1 binds to HGF by its HS moieties and promotes signaling through HGF receptor (Met) . Urokinase-type plasminogen activator ( PLAU) also cleavage HGF .
Upon binding ligands, tyrosine kinase receptors dimerize and autophosphorylate conservative residues in their cytoplasmic tail generating docking sites for intracellular signal transducers . 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 .
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 .
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  GAB1 recruits several important substrates to activated HGF receptor (Met), for example PLC-gamma , , Shc, SHP-2, CrkL, GRB2 and PI3K. Thereby, GAB1 amplifes HGF receptor (Met) signaling . PLC-gamma1 also can bind to HGF receptor (Met) directly (weak binding) .
Phosphorylated GAB1 binds CrkL. CrkL binds to Rap guanine nucleotide exchange factor 1 ( C3G) that activates GTPase Rap1 . CrkL also binds Dedicator of cytokinesis 2 ( DOCK2), an exchange factor for Ras-related C3 botulinum toxin substrate 1 ( Rac1 ) . Thus, in response to HGF, HGF receptor (Met) activates both Rap1 and Rac1, involved in cell adhesion, spreading, dissociation, and migration  CrkL can signal through Rac1 to activate JNK-signaling pathway . HGF mediates EMT via V-crk sarcoma virus CT10 oncogene homolog ( CRK ) and CrkL/ DOCK2 -mediated Rac1 activation , , . 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) , .
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 . H-Ras is required for epithelial adhesion junction disassembly induced by HGF through activation of both PI3K and ERK1/2 . 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 .
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) ) . 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 )) , . Activation of c-Fos transcription by ERK1/2 commonly performed via ELK1 member of ETS oncogene family ( Elk-1 ) . 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 .
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 , . 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 .
HGF can prevent apoptosis via direct binding and inhibition of FASR .
V-src sarcoma viral oncogene homolog ( c-Src ) activation is important for the HGF- mediated cell migration and cell transformation  c-Src induces phosphorylation and activation of Paxillin and Focal adhesion kinase ( FAK ) .