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Signaling pathways in the induction of c‐met receptor expression by its ligand scatter factor/hepatocyte growth factor in human glioblastoma
Author(s) -
Abounader R.,
Ranganathan S.,
Kim B. Y. S.,
Nichols C.,
Laterra J.
Publication year - 2001
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1046/j.1471-4159.2001.00158.x
Subject(s) - hepatocyte growth factor , mapk/erk pathway , biology , protein kinase c , microbiology and biotechnology , receptor tyrosine kinase , tyrosine kinase , signal transduction , cell culture , c met , hepatocyte growth factor receptor , transactivation , kinase , cancer research , chemistry , receptor , transcription factor , biochemistry , genetics , gene
Scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c‐met are developmentally expressed, neuroprotective, and tumorigenic within the CNS. In the present study SF/HGF is shown to induce the expression of c‐met in two human glioblastoma cell lines, U‐373 MG and T98G, and the signaling pathways involved in this induction are dissected. SF/HGF activated mitogen‐activated protein kinase (MAPK) and inhibition of either Ras or MAPK‐kinase completely inhibited SF/HGF‐mediated c‐met induction. Inhibition of phospholipase‐C (PLC) did not affect c‐met induction in either cell line. Inhibition of phosphoinositide 3‐kinase (PI3‐kinase) substantially reduced c‐met induction by SF/HGF in T98G cells but had no effect in U‐373 MG cells. Protein kinase C (PKC) inhibition reduced c‐met induction in T98G cells but not in U‐373 MG cells. SF/HGF induced the expression of c‐fos and c‐jun mRNA and increased the levels of AP‐1 transcription factor in both cells lines as determined by AP‐1‐luciferase reporter expression. Transfection of either cell line with TAM‐67, a dominant negative for the jun transactivation domain, completely inhibited AP‐1 and c‐met induction by SF/HGF. These results support a model of c‐met induction by SF/HGF in human glioma cells that uniformly involves Ras, MAPK, and AP‐1 and additionally involves PI3‐kinase and PKC in some cell lines.