Cross-talk between Epidermal Growth Factor Receptor and c-Met Signal Pathways in Transformed Cells

Abstract

In rat liver epithelial cells constitutively expressing transforming growth factor ␣ (TGF␣), c-Met is constitutively phosphorylated in the absence of its ligand, hepatocyte growth factor. We proposed that TGF␣ and the autocrine activation of its receptor, epidermal growth factor receptor (EGFR) Growth factor signal pathways are one of the main regulators of cell proliferation, differentiation, and apoptosis. Overexpression of receptors, aberrant expression of growth factor receptors such as truncated receptors, and co-expression of both growth factor ligands and their specific receptors within the same cell contribute to tumorigenesis. Transgenic mice which overexpress transforming growth factor ␣ developed hepatocellular carcinomas, epithelial hyperplasia, pancreatic metaplasia, and breast carcinoma (1-3) and autocrine expression of TGF␣ 1 is demonstrated in various human tumors and cell lines including cancers of the head and neck, lung, stomach, breast, ovary, uterine cervix, kidney, and liver (4 -7).,TGF␣ has a similar structure and function to epidermal growth factor (EGF). Both TGF␣ and EGF bind and activate the same receptor, EGFR, and thus induce a mitogenic and motogenic response in many cell types. EGFR is a transmembrane tyrosine kinase which is encoded by the proto-oncogene c-erb B and is expressed on most cell types. The activated EGFR dimerizes and autophosphorylates tyrosine residues and leads to a cascade of intracellular signaling pathways including the phosphoinositide 3-kinase (PI-3K) pathway, Ras-Raf-MAPK pathway, and phospholipase C pathway (8).Scatter factor/hepatocyte growth factor (HGF) was originally described as a mitogenic factor of hepatocytes during liver regeneration (9, 10), but HGF has a variety of additional biological activities including motogenesis (10) and morphogenesis (11) in many epithelial cells. HGF is essential for normal embryological development (12) and liver regeneration (13,14). The receptor of HGF, c-Met, is also a tyrosine kinase receptor (15), and the binding of its ligand to c-Met leads to the activation of the PI-3K pathway which activates motogenesis (16,17) and the Ras-Raf-MAPK pathway which is involved in mitogenesis (18). HGF pathway has also been found to activate both the STAT (19) and phospholipase C pathway. Spontaneously transformed tumor cell lines which express both HGF and c-Met show increased autonomous proliferation and motility (20). Also, overexpression of c-Met and its activation by autocrine HGF expression is found in a variety of human tumors indicating co-expression of HGF and c-Met may be involved in tumor metastasis (21,22).Previously, we reported that c-Met was phosphorylated in the absence of its ligand in TGF␣ transfectants of rat liver epithelial cells, and tumor clones derived from rat liver epithelial cells TGF␣ transfectants (23). We proposed that EGFR constitutively activated by autocrine TGF␣ expression results in cross-talk between these growth factor receptor systems resulting in constitutive phosphorylation of c-Met. Cross-tal...

PYK2 sustains endosomal-derived receptor signalling and enhances epithelial-to-mesenchymal transition

“…6b,d). These results are consistent with previous studies describing the crosstalk between EGFR and c-Met, and the ability of EGFR to trans-activate c-Met 58 .…”

EGFR is dispensable for c-Met-mediated proliferation and survival activities in mouse adult liver oval cells

“…3A). However, phosphorylated AKT and ERK1/2 were observed under both treatments, which is consistent with the fact that these Although bidirectional cross-talk between Met and EGFR might occur, a role for EGFR in Met-mediated signalling seems to be more established, particularly in hepatic cells [17,18,28]. Hence, we next tested the consequences of inhibiting the EGFR kinase on HGF-driven signalling.…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…MET co-immunoprecipitates with EGFR in protein extracts from HCC cells but not in extracts from normal hepatocytes, suggesting a new tumor-specific cross-talk for the activation of HGF/MET signaling by the TGFa/ EGFR axis (Jo et al, 2000).…”

“…In addition, somatic mutations in the tyrosine kinase domain have been detected in childhood HCCs (30%) but not in adult HCCs (Park et al, 1999). Furthermore, receptor transactivation by EGF receptor (EGFR) and RON (Follenzi et al, 2000;Jo et al, 2000) or cell/cell contact ) represent potential molecular mechanisms for ligand-independent activation of this signaling pathway. Similarly, HGF has been shown to be over represented in HCCs as compared to the normal liver; however, it is not expressed by tumor cells themselves (Selden et al, 1994;Noguchi et al, 1996).…”