A module of negative feedback regulators defines growth factor signaling.
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.
Amit
Ido
I
Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
Citri
Ami
A
Shay
Tal
T
Lu
Yiling
Y
Katz
Menachem
M
Zhang
Fan
F
Tarcic
Gabi
G
Siwak
Doris
D
Lahad
John
J
Jacob-Hirsch
Jasmine
J
Amariglio
Ninette
N
Vaisman
Nora
N
Segal
Eran
E
Rechavi
Gideon
G
Alon
Uri
U
Mills
Gordon B
GB
Domany
Eytan
E
Yarden
Yosef
Y
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
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