title: Phosphorylation of Groucho mediates RTK feedback inhibition and prolonged pathway target gene expression.
abstract: BACKGROUND
  Signaling by receptor tyrosine kinase (RTK) pathways plays fundamental roles in processes of cell-fate determination, often through the induction of specific transcriptional responses. Yet it is not fully understood how continuous target gene expression, required for irreversible cell-fate specification, is preserved after RTK signaling has ended. Here we address this question using the Drosophila embryo, a model system that has been instrumental in elucidating the developmental functions of RTK signal transduction.
  
  
  RESULTS
  The Groucho corepressor is phosphorylated and downregulated in response to RTK signaling. Here we show that RTK pathways use Groucho phosphorylation as a general mechanism for inducing expression of pathway target genes encoding cell-fate determinants as well as feedback antagonists, indicating that relief of Groucho-dependent repression is an integral element of RTK signaling networks. We further demonstrate that after mitogen-activated protein kinase (MAPK) has been deactivated, sustained phosphorylation of Groucho is essential for persistent RTK-induced target gene expression and cell-fate determination in several developmental contexts.
  
  
  CONCLUSIONS
  Phosphorylation of Groucho by MAPK plays a dual role in the regulation of RTK responses: (1) it mediates rapid feedback inhibition, and (2) it provides a stable memory mechanism of past MAPK activity. We propose that, in this manner, phosphorylation of Groucho enables transiently active RTK pathways to fix the spatiotemporal expression profiles of downstream targets over time.
authors.affiliation: Department of Developmental Biology and Cancer Research, Institute of Medical Research Israel-Canada, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel.
authors.forename: Aharon
authors.initials: A
authors.lastname: Helman
authors.forename: Einat
authors.initials: E
authors.lastname: Cinnamon
authors.forename: Sharon
authors.initials: S
authors.lastname: Mezuman
authors.forename: Zvi
authors.initials: Z
authors.lastname: Hayouka
authors.forename: Tonia
authors.initials: T
authors.lastname: Von Ohlen
authors.forename: Amir
authors.initials: A
authors.lastname: Orian
authors.forename: Gerardo
authors.initials: G
authors.lastname: Jiménez
authors.forename: Ze'ev
authors.initials: Z
authors.lastname: Paroush
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004330:Drosophila / Q000196:embryology / Q000235:genetics / Q000378:metabolism*; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D020935:MAP Kinase Signaling System; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D015398:Signal Transduction
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D020928:Mitogen-Activated Protein Kinases; D020794:Receptor Protein-Tyrosine Kinases; D012097:Repressor Proteins; C091023:gro protein, Drosophila