title: The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans.
abstract: Cell signaling pathways that control proliferation and determine cell fates are tightly regulated to prevent developmental anomalies and cancer. Transcription factors and coregulators are important effectors of signaling pathway output, as they regulate downstream gene programs. In Caenorhabditis elegans, several subunits of the Mediator transcriptional coregulator complex promote or inhibit vulva development, but pertinent mechanisms are poorly defined. Here, we show that Mediator's dissociable cyclin dependent kinase 8 (CDK8) module (CKM), consisting of cdk-8, cic-1/Cyclin C, mdt-12/dpy-22, and mdt-13/let-19, is required to inhibit ectopic vulval cell fates downstream of the epidermal growth factor receptor (EGFR)-Ras-extracellular signal-regulated kinase (ERK) pathway. cdk-8 inhibits ectopic vulva formation by acting downstream of mpk-1/ERK, cell autonomously in vulval cells, and in a kinase-dependent manner. We also provide evidence that the CKM acts as a corepressor for the Ets-family transcription factor LIN-1, as cdk-8 promotes transcriptional repression by LIN-1. In addition, we find that CKM mutation alters Mediator subunit requirements in vulva development: the mdt-23/sur-2 subunit, which is required for vulva development in wild-type worms, is dispensable for ectopic vulva formation in CKM mutants, which instead display hallmarks of unrestrained Mediator tail module activity. We propose a model whereby the CKM controls EGFR-Ras-ERK transcriptional output by corepressing LIN-1 and by fine tuning Mediator specificity, thus balancing transcriptional repression vs. activation in a critical developmental signaling pathway. Collectively, these data offer an explanation for CKM repression of EGFR signaling output and ectopic vulva formation and provide the first evidence of Mediator CKM-tail module subunit crosstalk in animals.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Grants
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
authors.forename: Lisa T L
authors.initials: LT
authors.lastname: Ying
authors.affiliation: Division of Neuroanatomy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan.
authors.forename: Akinori
authors.initials: A
authors.lastname: Yoda
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada.
authors.forename: Charlotte C
authors.initials: CC
authors.lastname: You
authors.affiliation: Division of Neuroanatomy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan Department of Physiology, Keio University School of Medicine, Tokyo, 108-8345, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Division of Neuroanatomy, Osaka University Graduate School of Medicine, Osaka, 565-0871, Japan Multicellular Organization Laboratory, National Institute of Genetics, Mishima, 411-0801, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Sawa
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada Centre for Molecular Medicine and Therapeutics, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, V5Z 4H4, Canada taubert@cmmt.ubc.ca.
authors.forename: Stefan
authors.identifier: http://orcid.org/0000-0002-2432-7257
authors.initials: S
authors.lastname: Taubert
mesh_terms: D000818:Animals; D017173:Caenorhabditis elegans / Q000235:genetics* / Q000378:metabolism*; D018844:Cyclin-Dependent Kinases / Q000737:chemistry / Q000378:metabolism*; D066246:ErbB Receptors / Q000378:metabolism*; D015870:Gene Expression; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D008954:Models, Biological; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D015398:Signal Transduction; D014158:Transcription, Genetic
chemical_list: D046912:Multiprotein Complexes; D066246:ErbB Receptors; D018844:Cyclin-Dependent Kinases
keywords: CDK8; EGFR; MED15; MED23; Mediator complex; Notch