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
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
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) .
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