Development - HGF signaling pathway

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:

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