title: Ras-Erk signaling induces phosphorylation of human TLE1 and downregulates its repressor function.
abstract: Signaling mediated by the Ras-extracellular signal-regulated kinase (Erk) pathway often leads to the phosphorylation of transcriptional regulators, thereby modulating their activity and causing concerted changes in gene expression. In Drosophila, the induction of multiple Ras-Erk pathway target genes depends on prior phosphorylation of the general co-repressor Groucho, a modification that downregulates its repressive function. Here, we show that TLE1, one of the four human Groucho orthologs, is similarly phosphorylated in response to Ras-Erk pathway activation, and that this modification attenuates its capacity to repress transcription. Specifically, unphosphorylated TLE1 dominantly suppresses the induction of Ras-Erk pathway target genes in cultured human cells, and the expression of an unphosphorylatable TLE1 derivative causes severe phenotypes in a transgenic Drosophila model system, whereas a phosphomimetic variant of TLE1 exerts only negligible effects. We present data indicating that TLE1 is rapidly excluded from the nucleus following epidermal growth factor receptor pathway activation, an effect that likely accounts for its inability to mediate effective repression under such conditions. Significantly, we find that unphosphorylated TLE1 blocks oncogenic phenotypes induced by mutated H-Ras in human mammary cells, both in vitro and following their implantation in mice. Collectively, our data strongly indicate that phosphorylation of TLE family members and the consequent downregulation of their repressor function is a key conserved step in the transcriptional responses to Ras-Erk signaling, and possibly a critical event in the tumorigenic effects caused by excessive Ras-Erk pathway activity.
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Zahavi
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: A
authors.initials: A
authors.lastname: Maimon
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: T
authors.initials: T
authors.lastname: Kushnir
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Lange
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Berger
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.|Department of Oncology, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: D
authors.initials: D
authors.lastname: Kornspan
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: R
authors.initials: R
authors.lastname: Grossman
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: S
authors.initials: S
authors.lastname: Anzi
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: E
authors.initials: E
authors.lastname: Shaulian
authors.affiliation: Department of Biochemistry and Molecular Biology, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: R
authors.identifier: 0000-0002-7552-9617
authors.initials: R
authors.lastname: Karni
authors.affiliation: Department of Oncology, Sharett Institute of Oncology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: H
authors.initials: H
authors.lastname: Nechushtan
authors.affiliation: Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.
authors.forename: Z
authors.initials: Z
authors.lastname: Paroush
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D002454:Cell Differentiation / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D056970:Co-Repressor Proteins; D015536:Down-Regulation; D004330:Drosophila; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006367:HeLa Cells; D064593:Heterografts; D006801:Humans; D020935:MAP Kinase Signaling System; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D018631:ras Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D056970:Co-Repressor Proteins; D012097:Repressor Proteins; C499043:TLE1 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D048049:Extracellular Signal-Regulated MAP Kinases; D018631:ras Proteins