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A module of negative feedback regulators defines growth factor signaling

Nature Genetics volume 39, pages 503–512 (2007)Cite this article

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.

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Figure 1: MAPKs are a node of transcription-dependent feedback regulation.
Figure 2: Circuitry of growth factor–induced transcriptional regulation.
Figure 3: The delayed early genes MAFF, KLF2 and KLF6 repress EGF-driven gene transcription.
Figure 4: Induction of the ZFP36 ensures rapid degradation of transiently induced genes.
Figure 5: Transcription-repressor and RNA-binding DEGs are coordinately downregulated in multiple human tumors.
Figure 6: A common architecture underlies gene expression programs activated by stimulation of MCF10A cells with EGF or serum.
Figure 7: Pathway-specific induction of DUSPs.
Figure 8: Potential network motifs used by the EGF-induced transcription program.

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Acknowledgements

We thank P. Blackshear, W. Lai, M. Kracht, J. Milbrandt, S. Friedman and G. Narla for reagents. We thank P. Luu, R. Malenka and N. Citri for instructive comments on the manuscript. We thank W.L. Gerald for providing us with the prostate cancer data set. The following plasmids were gifts: ZFP36-GFP from P. Blackshear (National Institutes of Health), an IL8 reporter plasmid from M. Kracht (Medical School Hannover), EGR1 reporter plasmid from J. Milbrandt (Washington University School of Medicine) and a STAT3 reporter plasmid from A. Gertler (Hebrew University). Our laboratory is supported by research grants from Minerva, the Israel Cancer Research Fund, the German Israel Foundation, the Prostate Cancer Foundation, the European Commission and the National Cancer Institute (grants CA72981, CA102537, CA65930, CA64602 and CA099031). Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair, and E.D. is the incumbent of the Henry J. Leir Professorial Chair. A.C. acknowledges support of the Human Frontier Science Program. E.D. was supported in part by the Ridgefield Foundation, the Israel Science Fund and the European Commission (EC FP6). Requests for materials should be addressed to Y.Y. (yosef.yarden@weizmann.ac.il).

Author information

Author notes

  1. Ami Citri

    Present address: Current address: Department of Psychiatry and Behavioral Sciences, Stanford University Medical School, Palo Alto, California 94304-5485, USA.,

  2. Ido Amit and Ami Citri: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biological Regulation, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Ido Amit, Ami Citri, Menachem Katz, Gabi Tarcic & Yosef Yarden

  2. Department of Physics of Complex Systems, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Tal Shay & Eytan Domany

  3. Department of Systems Biology, MD Anderson Cancer Center, Houston, 77030, Texas, USA

    Yiling Lu, Fan Zhang, Doris Siwak, John Lahad & Gordon B Mills

  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

    Jasmine Jacob-Hirsch, Ninette Amariglio & Gideon Rechavi

  5. Sigma-Aldrich Israel, Ltd., Rehovot, 76100, Israel

    Nora Vaisman

  6. Department of Computer Science, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Eran Segal

  7. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, 76100, Israel

    Uri Alon

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Supplementary information

Supplementary Fig. 1

Model illustrating circuitries of feedback regulation embedded in the EGF-induced transcriptional program. (PDF 188 kb)

Supplementary Fig. 2

Ligands and cytokines induced by EGF in HeLa cells. (PDF 62 kb)

Supplementary Fig. 3

The repressive functions of MAFF and KLF2 depend on integrity of their effector domains. (PDF 354 kb)

Supplementary Fig. 4

ZFP36 governs stability of EGF-induced transcripts. (PDF 529 kb)

Supplementary Fig. 5

EGF-induced ligands and cytokines are coordinately upregulated in tumors of ovarian patients. (PDF 79 kb)

Supplementary Fig. 6

EGF and serum induce different subsets of transcription regulators and cytokines in MCF10A cells. (PDF 74 kb)

Supplementary Fig. 7

Additional potential network motifs used by the EGF-induced transcriptional program. (PDF 68 kb)

Supplementary Table 1

Phosphoprotein and gene expression profiles of EGF-stimulated epithelial cells. (PDF 183 kb)

Supplementary Methods (PDF 110 kb)

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Amit, I., Citri, A., Shay, T. et al. A module of negative feedback regulators defines growth factor signaling. Nat Genet 39, 503–512 (2007). https://doi.org/10.1038/ng1987

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