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Development HGF signaling pathway

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Development HGF signaling pathway

HGF signaling

Hepatocyte growth factor/Scatter factor ( HGF/SF) is a multifunctional growthfactor which induce a diverse biological response including cell dissociation, migration,protection from apoptosis, proliferation and differentiation [1].

The product of proto-oncogene MET is the hepatocyte growth factor receptor withtyrosine-kinase activity.

HGF is produced primarily by mesenchymal cells and secreted as an inactivezymogen which must be cleaved by a serine protease to initiate MET signaling.HGF-specific serine protease is known as HGF activator ( HGFA ) [2].Syndecan-1 binds to HGF by its HS moieties and promotes signaling throughMET [3]. Urokinase-type plasminogen activator ( PLAU) alsocleavage HGF [4]. Met is predominantly expressed in the cellsof epithelial or endothelial origin.

Upon binding their ligands ty rosine kinase receptors dimerize and autophosphorylateconservative residues in their cytoplasmic tail generating docking sites forintracellular signal transducers [5]. The multisubstrate docking sitemediates binding of several adapter proteins such as Growth factor receptor-boundprotein 2 ( Grb2), SHC transforming protein 1 (Shc), v-crk sarcoma virusCT10 oncogene homolog (avian)-like ( Crk/ CRKL), GRB2-associated bindingprotein 1 ( GAB1) the regulatory subunit of Phosphatidylinositol-3-kinase (PI3K reg class 1A ), tyrosine-protein kinase SRC, Phospholipase C gamma 1( PLC-gamma1 ), phosphatase SHP-2 and transcriptional factor STAT3,thereby activating different signal cascades [6].

GAB1, a large scaffold adaptor protein, is phosphorylated in association withthe activated Met. Gab1 is responsible for HGF/SF-Met-induced scatteringand branching morphogenesis of epithelial cells [5] GAB1 recruitsseveral important substrates to activated Met including PLC-gamma, Shc,SHP-2, CRKL, Grb2 and PI3K. Thereby, GAB1 amplifes Metsignaling [5].

PLC-gamma1 binds to Met directly (weak binding) [7], butmainly, activation of PLC-gamma1 is mediated by GAB1 [1].

PI3K activation proceeds via recruitment of its regulatory subunits. ActivePI3K produces phosphatidylinositol 3,4,5-triphosphate ( PI(3,4,5)P3 ), the second messenger involved in regulation of multiple cellularprocesses [8], [5].

Adaptor Grb2 associates with son of sevenless homologes ( SOS ) andcouples Met with v-Ha-ras Harvey rat sarcoma viral oncogene homolog ( H-RAS)/ v-raf-1 murine leukemia viral oncogene homolog 1 ( c-RAF )/ Mitogen-activatedprotein kinase kinases 1 and 2 ( MEK1 and MEK2 )/ Mitogen-activatedprotein kinases 3 and 1 ( ERK1 and ERK2 ) to the interaction withH-RAS (and thus to the downstream mitogen-activated protein kinase pathway) ismandatory for the consequential cell proliferation [1]. H-RAS isrequired for epithelial adhesion junction disassembly induced by HGF/SF throughactivation of both PI3K and ERK1/2 [5].

CRKL protein is a Crk family member which binds to phosphorylated GAB1and adds an array of signal transducers that become activated upon HGF/SF stimulation.CRKL binds to Rap guanine nucleotide exchange factor 1 ( C3G) thatactivates GTPase Rap1 from Ras superfamily [9]. CRKL alsobinds Dedicator of cytokinesis 2 ( DOCK2), an exchange factor for Ras-related C3botulinum toxin substrate 1 ( Rac1 ) [10]. Thus, in response toHGF, Met activates both Rap1 and Rac1, involved in celladhesion, spreading, dissociation, and migration [11] CRKL can signalthrough Rac1 to activate JNK-signaling pathway [12].

HGF stimulates recruitment of Signal transducer and activator of transcription3 ( STAT3 ) to the receptor, tyrosine phosphorylation, nuclear translocation andbinding to the specific promoter element [13].

v-src sarcoma viral oncogene homolog ( c-Src ) activation is important for theHGF/SF-Met mediated cell migration and cell transformation [11]c-Src induces phosphorylation and activation of Paxillin and Focal adhesionkinase ( FAK ) [5].

HGF is also a potent anti-apoptotic factor, a function realized via differentpathways. One pathway proceeds via direct binding and inhibition of FASR [14]. Another one is known as suspension-induced apoptosis. HGF -mediatedinhibition of anoikis. This pathway proceeds via activation of transcriptional factorAP-1 by ERK -signaling pathway, followed by AP-1 activation oftranscription of Cyclooxygenase-2 ( COX-2 ) [15].