title: Gene regulation by MAPK substrate competition.
abstract: Developing tissues are patterned by coordinated activities of signaling systems, which can be integrated by a regulatory region of a gene that binds multiple transcription factors or by a transcription factor that is modified by multiple enzymes. Based on a combination of genetic and imaging experiments in the early Drosophila embryo, we describe a signal integration mechanism that cannot be reduced to a single gene regulatory element or a single transcription factor. This mechanism relies on an enzymatic network formed by mitogen-activated protein kinase (MAPK) and its substrates. Specifically, anteriorly localized MAPK substrates, such as Bicoid, antagonize MAPK-dependent downregulation of Capicua, a repressor that is involved in gene regulation along the dorsoventral axis of the embryo. MAPK substrate competition provides a basis for ternary interaction of the anterior, dorsoventral, and terminal patterning systems. A mathematical model of this interaction can explain gene expression patterns with both anteroposterior and dorsoventral polarities.
authors.affiliation: Department of Chemical and Biological Engineering, Lewis-Sigler Institute for Integrative Genomics, Princeton University, NJ 08544, USA.
authors.forename: Yoosik
authors.initials: Y
authors.lastname: Kim
authors.forename: María José
authors.initials: MJ
authors.lastname: Andreu
authors.forename: Bomyi
authors.initials: B
authors.lastname: Lim
authors.forename: Kwanghun
authors.initials: K
authors.lastname: Chung
authors.forename: Mark
authors.initials: M
authors.lastname: Terayama
authors.forename: Gerardo
authors.initials: G
authors.lastname: Jiménez
authors.forename: Celeste A
authors.initials: CA
authors.lastname: Berg
authors.forename: Hang
authors.initials: H
authors.lastname: Lu
authors.forename: Stanislav Y
authors.initials: SY
authors.lastname: Shvartsman
mesh_terms: D000818:Animals; D029721:Drosophila Proteins / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000196:embryology / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D024002:HMGB Proteins / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008962:Models, Theoretical; D010766:Phosphorylation; D012097:Repressor Proteins / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators / Q000378:metabolism*
chemical_list: D029721:Drosophila Proteins; D024002:HMGB Proteins; D018398:Homeodomain Proteins; D012097:Repressor Proteins; D015534:Trans-Activators; C085607:Zen protein, Drosophila; C056478:bcd protein, Drosophila; C404284:cic protein, Drosophila; D020928:Mitogen-Activated Protein Kinases