PMID- 11948414 OWN - NLM STAT- MEDLINE DCOM- 20020429 LR - 20220310 IS - 0950-9232 (Print) IS - 0950-9232 (Linking) VI - 21 IP - 15 DP - 2002 Apr 4 TI - Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. PG - 2309-19 AB - Hepatocyte growth factor/scatter factor (HGF/SF) induces scattering and morphogenesis of epithelial cells through the activation of the MET tyrosine kinase receptor. Although the activated MET receptor recruits a number of signaling proteins, little is known of the downstream signaling pathways activated by HGF/SF. In this study, we wished to examine the signaling pathway leading to activation of the ETS1 transcription factor. Using in vitro and in vivo kinase assays, we found that HGF/SF activates the ERK1 MAP kinase, leading to the phosphorylation of the threonine 38 residue of ETS1 within a putative MAP kinase phosphorylation site (PLLT38P). This threonine residue was neither phosphorylated by JNK1, nor by p38 MAP kinases and was required for the induction of transcriptional activity of ETS1 by HGF/SF. Using kinase and transcription assays, we further demonstrated that phosphorylation and activation of ETS1 occurs downstream of a RAS-RAF-MEK-ERK pathway. The functional involvement of this pathway in HGF/SF action was demonstrated using U0126, a pharmacological inhibitor of MEK, which blocked phosphorylation and activation of ETS1, RAS-dependent transcriptional responses, cell scattering and morphogenesis. These data demonstrated that ETS1 is a downstream target of HGF/SF acting through a RAS-RAF-MEK-ERK pathway and provides a signaling pathway leading to the regulation of gene expression by HGF/SF. FAU - Paumelle, Rejane AU - Paumelle R AD - CNRS FRE 2353, Institut de Biologie de Lille, Institut Pasteur de Lille, B.P.447, 59021 Lille, France. FAU - Tulasne, David AU - Tulasne D FAU - Kherrouche, Zoulika AU - Kherrouche Z FAU - Plaza, Serge AU - Plaza S FAU - Leroy, Catherine AU - Leroy C FAU - Reveneau, Sylvie AU - Reveneau S FAU - Vandenbunder, Bernard AU - Vandenbunder B FAU - Fafeur, Veronique AU - Fafeur V LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PL - England TA - Oncogene JT - Oncogene JID - 8711562 RN - 0 (Proto-Oncogene Protein c-ets-1) RN - 0 (Proto-Oncogene Proteins) RN - 0 (Proto-Oncogene Proteins c-ets) RN - 0 (Transcription Factors) RN - 1114-81-4 (Phosphothreonine) RN - 67256-21-7 (Hepatocyte Growth Factor) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-raf) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 3) RN - EC 2.7.11.24 (Mitogen-Activated Protein Kinases) RN - EC 2.7.12.2 (Mitogen-Activated Protein Kinase Kinases) RN - EC 3.6.5.2 (Proto-Oncogene Proteins p21(ras)) SB - IM EIN - Oncogene 2002 Jul 18;21(31):4872. Tulashe, David [corrected to Tulasne, David]; Reveneau, Syline [corrected to Reveneau, Sylvie] MH - Animals MH - Cell Line MH - Dogs MH - Epithelial Cells/cytology/drug effects/metabolism MH - Hepatocyte Growth Factor/*pharmacology MH - *MAP Kinase Signaling System/drug effects MH - Mitogen-Activated Protein Kinase 3 MH - Mitogen-Activated Protein Kinase Kinases/metabolism MH - Mitogen-Activated Protein Kinases/metabolism MH - Morphogenesis MH - Phosphorylation MH - Phosphothreonine/metabolism MH - Proto-Oncogene Protein c-ets-1 MH - Proto-Oncogene Proteins/chemistry/*metabolism MH - Proto-Oncogene Proteins c-ets MH - Proto-Oncogene Proteins c-raf/metabolism MH - Proto-Oncogene Proteins p21(ras)/metabolism MH - Transcription Factors/chemistry/*metabolism MH - Transcriptional Activation EDAT- 2002/04/12 10:00 MHDA- 2002/05/01 10:01 CRDT- 2002/04/12 10:00 PHST- 2001/07/16 00:00 [received] PHST- 2002/01/02 00:00 [revised] PHST- 2002/01/08 00:00 [accepted] PHST- 2002/04/12 10:00 [pubmed] PHST- 2002/05/01 10:01 [medline] PHST- 2002/04/12 10:00 [entrez] AID - 10.1038/sj.onc.1205297 [doi] PST - ppublish SO - Oncogene. 2002 Apr 4;21(15):2309-19. doi: 10.1038/sj.onc.1205297.