title: A module of negative feedback regulators defines growth factor signaling.
abstract: Signaling pathways invoke interplays between forward signaling and feedback to drive robust cellular response. In this study, we address the dynamics of growth factor signaling through profiling of protein phosphorylation and gene expression, demonstrating the presence of a kinetically defined cluster of delayed early genes that function to attenuate the early events of growth factor signaling. Using epidermal growth factor receptor signaling as the major model system and concentrating on regulation of transcription and mRNA stability, we demonstrate that a number of genes within the delayed early gene cluster function as feedback regulators of immediate early genes. Consistent with their role in negative regulation of cell signaling, genes within this cluster are downregulated in diverse tumor types, in correlation with clinical outcome. More generally, our study proposes a mechanistic description of the cellular response to growth factors by defining architectural motifs that underlie the function of signaling networks.
authors.affiliation: Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ido
authors.initials: I
authors.lastname: Amit
authors.forename: Ami
authors.initials: A
authors.lastname: Citri
authors.forename: Tal
authors.initials: T
authors.lastname: Shay
authors.forename: Yiling
authors.initials: Y
authors.lastname: Lu
authors.forename: Menachem
authors.initials: M
authors.lastname: Katz
authors.forename: Fan
authors.initials: F
authors.lastname: Zhang
authors.forename: Gabi
authors.initials: G
authors.lastname: Tarcic
authors.forename: Doris
authors.initials: D
authors.lastname: Siwak
authors.forename: John
authors.initials: J
authors.lastname: Lahad
authors.forename: Jasmine
authors.initials: J
authors.lastname: Jacob-Hirsch
authors.forename: Ninette
authors.initials: N
authors.lastname: Amariglio
authors.forename: Nora
authors.initials: N
authors.lastname: Vaisman
authors.forename: Eran
authors.initials: E
authors.lastname: Segal
authors.forename: Gideon
authors.initials: G
authors.lastname: Rechavi
authors.forename: Uri
authors.initials: U
authors.lastname: Alon
authors.forename: Gordon B
authors.initials: GB
authors.lastname: Mills
authors.forename: Eytan
authors.initials: E
authors.lastname: Domany
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
mesh_terms: D062565:Acid Sensing Ion Channels; D002478:Cells, Cultured; D016000:Cluster Analysis; D062626:Degenerin Sodium Channels; D004815:Epidermal Growth Factor / Q000502:physiology; D053503:Epithelial Sodium Channels / Q000502:physiology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000502:physiology; D025461:Feedback, Physiological / Q000235:genetics*; D005786:Gene Expression Regulation; D006367:HeLa Cells; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology*; D051741:Kruppel-Like Transcription Factors / Q000502:physiology; D051260:MafF Transcription Factor / Q000502:physiology; D008954:Models, Biological; D009419:Nerve Tissue Proteins / Q000502:physiology; D009687:Nuclear Proteins / Q000502:physiology; D015398:Signal Transduction / Q000235:genetics*; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*; D051816:Tristetraprolin / Q000502:physiology
chemical_list: C568424:ASIC2 protein, human; D062565:Acid Sensing Ion Channels; D062626:Degenerin Sodium Channels; D053503:Epithelial Sodium Channels; D036341:Intercellular Signaling Peptides and Proteins; C096161:KLF2 protein, human; D051741:Kruppel-Like Transcription Factors; C484147:MAFF protein, human; D051260:MafF Transcription Factor; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; D014157:Transcription Factors; D051816:Tristetraprolin; C497552:ZFP36 protein, human; D004815:Epidermal Growth Factor; D048049:Extracellular Signal-Regulated MAP Kinases