A module of negative feedback regulators defines growth factor signaling

Ido Amit, Ami Citri, Tal Shay, Yiling Lu, Menachem Katz, Fan Zhang, Gabi Tarcic, Doris Siwak, John Lahad, Jasmine Jacob-Hirsch, Ninette Amariglio, Nora Vaisman, Eran Segal, Gideon Rechavi, Uri Alon, Gordon B. Mills, Eytan Domany, Yosef Yarden*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

396 Scopus citations

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.

Original languageEnglish
Pages (from-to)503-512
Number of pages10
JournalNature Genetics
Volume39
Issue number4
DOIs
StatePublished - Apr 2007

Funding

FundersFunder number
EC FP6
German Israel Foundation
Israel Science Fund
Ridgefield Foundation
National Cancer InstituteCA64602, CA099031, CA65930, CA102537, R37CA072981
National Cancer Institute
Prostate Cancer Foundation
Israel Cancer Research Fund
Human Frontier Science Program
European Commission

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