HGF Signaling

Pathway

Pathway Description

Hepatocyte Growth Factor (HGF) is a multipotent cytokine that stimulates cell proliferation, differentiation, motility and invasiveness. At the tissue level, HGF induces angiogenesis, hematopoiesis, chondrogenesis and also supports organogenesis. HGF is a natural ligand for the c-Met proto-oncogene product of receptor tyrosine kinase. Binding of HGF induces Met dimerization and autophosphorylation of two tyrosine residues. These phosphotyrosines mediate high-affinity interactions with various cytoplasmic effectors, which then transduce extracellular signals elicited by HGF to downstream targets.One of the major substrates of the activated HGF receptor tyrosine kinases is the adaptor protein GAB1. Phosphorylated GAB1 binds signal-relay molecules, such as the SH2-domain-containing proteins: SHP2, PI3K, PLC-γ, STAT3 and CrkL, through their SH2 domains. GAB1 interacts with CrkL, a protein with SH2 and SH3 protein interaction domains that couples to signaling further downstream. The actions of HGF on Pxn, DOCK1 and Rap1 which alter cell motility are also mediated through GAB1. CrkL can associate with, and activate multiple effector proteins, like DOCK1, C3G and GDP-GTP exchange factor for Rap1. C3G is implicated in the activation of Rap1, which further activates FAK and Pxn, associated with integrin.

Activated Met can specifically recruit GRB2, an adaptor protein that couples activated receptor tyrosine kinases to SOS, promoting activation of Ras. GAB1 contributes to Ras activation through activation of SHP2. Activation of Ras by HGF results in activation of Raf1, followed by the subsequent threonine and tyrosine phosphorylation of cytoplasmic dual specificity kinases, MEK1/2 which in turn activate ERK1/2. Major substrates for ERKs are the transcription factors Elk1 and Ets, which upon activation, up-regulate the expression of immediate early response genes, such as c-Fos. The ERKs also stimulate the stress-responsive transcription factors: c-Jun and c-Fos, found to be important in HGF-mediated survival.

Regulation of Rac1 and CDC42 pathways in response to HGF all contribute to cytoskeletal rearrangement and the subsequent changes in cellular motility. HGF functions as a scattering factor for epithelial cells, and this ability is mediated through the activation of STAT3. Phosphorylation of STAT3 and the resulting nuclear signaling alters cellular transcription in addition to altering cell adhesion, proliferation and cell motility required for triggering differentiation for branching morphogenesis. HGF also contributes to cell survival and differentiation by activating the MEKK-MEK4/7-JNK pathway. COX2 expression by HGF inhibits the process of Anoikis, a term used to describe apoptosis of epithelial cells induced by loss of matrix attachment. This process is important for maintaining normal cell and tissue homeostasis.

Protection of cells against DNA damage by HGF is mediated by a pathway from its receptor c-Met to PI3K via activation of GAB1- Akt-PAK1, resulting in enhanced DNA repair and decreased apoptosis. Activation of PAK1 also inhibits Anoikis. Activation of the Met receptor also results in an increase in receptor-mediated activation of PLC-γ which catalyzes the generation of IP3 and DAG from PIP2, which act as second messenger molecules to mobilize intracellular calcium and activate PKC respectively. These signaling pathways act as important components of the cell survival and cell migratory response.

The Met tyrosine kinase is shown to be deregulated through gene amplification, overexpression activating point mutations in human cancers. Mechanisms of HGF gene therapy implicate against graft failure, restenosis, cardiomyopathy, cerebral vascular diseases, renal failure etc.