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.
Bibliographical noteFunding Information:
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. (email@example.com).