Article abstract

Nature Genetics 39, 503 - 512 (2007)
Published online: 25 February 2007 | doi:10.1038/ng1987

A module of negative feedback regulators defines growth factor signaling

Ido Amit1,9, Ami Citri1,8,9, Tal Shay2, Yiling Lu3, Menachem Katz1, Fan Zhang3, Gabi Tarcic1, Doris Siwak3, John Lahad3, Jasmine Jacob-Hirsch4, Ninette Amariglio4, Nora Vaisman5, Eran Segal6, Gideon Rechavi4, Uri Alon7, Gordon B Mills3, Eytan Domany2 & Yosef Yarden1

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.

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot 76100, Israel.
  2. Department of Physics of Complex Systems, The Weizmann Institute of Science, Rehovot 76100, Israel.
  3. Department of Systems Biology, MD Anderson Cancer Center, Houston, Texas 77030, USA.
  4. Department of Pediatric Hemato-Oncology and Functional Genomics, The Chaim Sheba Medical Center and Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel.
  5. Sigma-Aldrich Israel, Ltd., Rehovot 76100, Israel.
  6. Department of Computer Science, The Weizmann Institute of Science, Rehovot 76100, Israel.
  7. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel.
  8. Current address: Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Palo Alto, California 94304-5485, USA.
  9. These authors contributed equally to this work.

Correspondence to: Yosef Yarden1 e-mail:


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