The epidermal growth factor receptor (EGFR)/ERBB family has evolved from a primordial, simple pathway of a single ligand receptor pair to a complex signalling network. Studies in invertebrates and in mammalian systems have unveiled a web of activity-dependent regulatory loops, which fall into early and late groups.
In the early phase, ubiquitylation and other covalent modifications that control receptor degradation, as well as primary and secondary (backward) phosphorylation, have major roles in the immediate regulation of receptor signalling. This phase also includes very rapid turnover of a group of microRNAs (miRNAs).
Late regulatory mechanisms of the network comprise newly induced mRNAs, miRNAs and proteins, which account for the specificity of the response to external stimuli.
The dynamic behaviour of the EGFR network and similar signalling systems identifies feedback and feedforward loops as a computational core able to perform complex tasks, such as digitalization of graded signals, filtration of noise, calculation of fold induction and fixation of output. This leads to stable phenotypes.
Cancer and other hyperproliferation diseases harness the regulatory mechanisms of the network by weakening negative feedback and enhancing positive feedback, thereby manipulating critical time constants of the network.
Human-made information relay systems invariably incorporate central regulatory components, which are mirrored in biological systems by dense feedback and feedforward loops. This type of system control is exemplified by positive and negative feedback loops (for example, receptor endocytosis and dephosphorylation) that enable growth factors and receptor Tyr kinases of the epidermal growth factor receptor (EGFR)/ERBB family to regulate cellular function. Recent studies show that the collection of feedback regulatory loops can perform computational tasks — such as decoding ligand specificity, transforming graded input signals into a digital output and regulating response kinetics. Aberrant signal processing and feedback regulation can lead to defects associated with pathologies such as cancer.
Subscribe to Journal
Get full journal access for 1 year
only $4.92 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Tax calculation will be finalised during checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Levi-Montalcini, R. & Cohen, S. Effects of the extract of the mouse submaxillary salivary glands on the sympathetic system of mammals. Ann. N. Y. Acad. Sci. 85, 324–341 (1960).
Cohen, S., Carpenter, G. & King, L. Jr. Epidermal growth factor-receptor-protein kinase interactions. Co-purification of receptor and epidermal growth factor-enhanced phosphorylation activity. J. Biol. Chem. 255, 4834–4842 (1980).
Ullrich, A. et al. Human epidermal growth factor receptor cDNA sequence and aberrant expression of the amplified gene in A431 epidermoid carcinoma cells. Nature 309, 418–425 (1984).
Hunter, T. Tyrosine phosphorylation: thirty years and counting. Curr. Opin. Cell Biol. 21, 140–146 (2009).
Pawson, T. & Scott, J. D. Signaling through scaffold, anchoring, and adaptor proteins. Science 278, 2075–2080 (1997).
Citri, A. & Yarden, Y. EGF-ERBB signalling: towards the systems level. Nature Rev. Mol. Cell Biol. 7, 505–516 (2006).
Kholodenko, B. N. Cell-signalling dynamics in time and space. Nature Rev. Mol. Cell Biol. 7, 165–176 (2006).
Oda, K., Matsuoka, Y., Funahashi, A. & Kitano, H. A comprehensive pathway map of epidermal growth factor receptor signaling. Mol. Syst. Biol. 1, 20050010 (2005). Presents a comprehensive pathway map of EGFR signalling. The map reveals that the overall architecture of the pathway is a bow-tie structure with several feedback loops.
Freeman, M. Feedback control of intercellular signalling in development. Nature 408, 313–319 (2000).
Xiong, W. & Ferrell, J. E. Jr. A positive-feedback-based bistable 'memory module' that governs a cell fate decision. Nature 426, 460–465 (2003). Shows that a brief exposure of frog oocytes to progesterone irreversibly triggers their maturation through a positive-feedback loop involving the MAPK cascade. However, the response becomes transient when positive feedback is blocked.
Kitano, H. Biological robustness. Nature Rev. Genet. 5, 826–837 (2004).
Kholodenko, B. N., Hancock, J. F. & Kolch, W. Signalling ballet in space and time. Nature Rev. Mol. Cell Biol. 11, 414–426 (2010).
Lemmon, M. A. & Schlessinger, J. Cell signaling by receptor tyrosine kinases. Cell 141, 1117–1134 (2010).
Jacob, F. & Monod, J. Genetic regulatory mechanisms in the synthesis of proteins. J. Mol. Biol. 3, 318–356 (1961).
Waddington, C. H. Canalization of development and the inheritance of acquired characters. Nature 150, 563–565 (1942).
Carpenter, G. & Cohen, S. 125I-labeled human epidermal growth factor. Binding, internalization, and degradation in human fibroblasts. J. Cell Biol. 71, 159–171 (1976).
Grimes, M. L., Beattie, E. & Mobley, W. C. A signaling organelle containing the nerve growth factor-activated receptor tyrosine kinase, TrkA. Proc. Natl Acad. Sci. USA 94, 9909–9914 (1997).
Vieira, A. V., Lamaze, C. & Schmid, S. L. Control of EGF receptor signaling by clathrin-mediated endocytosis. Science 274, 2086–2089 (1996).
Fehrenbacher, N., Bar-Sagi, D. & Philips, M. Ras/MAPK signaling from endomembranes. Mol. Oncol. 3, 297–307 (2009).
Goh, L. K., Huang, F., Kim, W., Gygi, S. & Sorkin, A. Multiple mechanisms collectively regulate clathrin-mediated endocytosis of the epidermal growth factor receptor. J. Cell Biol. 189, 871–883 (2010). Demonstrates, using receptor mutagenesis, that clathrin-dependent internalization of EGFR is regulated by four mechanisms: ubiquitylation of the receptor kinase domain, the clathrin adaptor complex AP2, the GRB2 adaptor protein and acetylation of three C-terminal Lys residues.
Sigismund, S. et al. Clathrin-mediated internalization is essential for sustained EGFR signaling but dispensable for degradation. Dev. Cell 15, 209–219 (2008). Reports that EGFRs internalized via clathrin-mediated endocytosis are recycled to the cell surface and their signalling is prolonged. By contrast, clathrin-independent internalization preferentially commits the receptor to degradation.
Huang, F., Kirkpatrick, D., Jiang, X., Gygi, S. & Sorkin, A. Differential regulation of EGF receptor internalization and degradation by multiubiquitination within the kinase domain. Mol. Cell 21, 737–748 (2006).
Levkowitz, G. et al. Ubiquitin ligase activity and tyrosine phosphorylation underlie suppression of growth factor signaling by c-Cbl/Sli-1. Mol. Cell 4, 1029–1040 (1999).
Frosi, Y. et al. A two-tiered mechanism of EGFR inhibition by RALT/MIG6 via kinase suppression and receptor degradation. J. Cell Biol. 189, 557–571 (2010).
Joazeiro, C. A. et al. The tyrosine kinase negative regulator c-Cbl as a RING-type, E2-dependent ubiquitin-protein ligase. Science 286, 309–312 (1999).
Oved, S. et al. Conjugation to Nedd8 instigates ubiquitylation and down-regulation of activated receptor tyrosine kinases. J. Biol. Chem. 281, 21640–21651 (2006).
Mosesson, Y. et al. Endocytosis of receptor tyrosine kinases is driven by monoubiquitylation, not polyubiquitylation. J. Biol. Chem. 278, 21323–21326 (2003).
Haglund, K. et al. Multiple monoubiquitination of RTKs is sufficient for their endocytosis and degradation. Nature Cell Biol. 5, 461–466 (2003).
Katzmann, D. J., Odorizzi, G. & Emr, S. D. Receptor downregulation and multivesicular-body sorting. Nature Rev. Mol. Cell Biol. 3, 893–905 (2002).
Polo, S. et al. A single motif responsible for ubiquitin recognition and monoubiquitination in endocytic proteins. Nature 416, 451–455 (2002).
Roepstorff, K. et al. Differential effects of EGFR ligands on endocytic sorting of the receptor. Traffic 10, 1115–1127 (2009).
Abella, J. V. & Park, M. Breakdown of endocytosis in the oncogenic activation of receptor tyrosine kinases. Am. J. Physiol. Endocrinol. Metab. 296, E973–E984 (2009).
Wang, Y. et al. Regulation of endocytosis via the oxygen-sensing pathway. Nature Med. 15, 319–324 (2009).
McMahon, H. T. & Gallop, J. L. Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature 438, 590–596 (2005).
Merrifield, C. J., Feldman, M. E., Wan, L. & Almers, W. Imaging actin and dynamin recruitment during invagination of single clathrin-coated pits. Nature Cell Biol. 4, 691–698 (2002).
Deribe, Y. L. et al. Regulation of epidermal growth factor receptor trafficking by lysine deacetylase HDAC6. Sci. Signal. 2, ra84 (2009). Reports that HDAC6 negatively regulates EGFR endocytosis and degradation by controlling the acetylation of α-tubulin. A negative-feedback loop consisting of EGFR-mediated phosphorylation of HDAC6 resulted in reduced deacetylase activity.
Jozic, D. et al. Cbl promotes clustering of endocytic adaptor proteins. Nature Struct. Mol. Biol. 12, 972–979 (2005).
Clague, M. J. & Urbe, S. Endocytosis: the DUB version. Trends Cell Biol. 16, 551–559 (2006).
McCullough, J. et al. Activation of the endosome-associated ubiquitin isopeptidase AMSH by STAM, a component of the multivesicular body-sorting machinery. Curr. Biol. 16, 160–165 (2006).
Niendorf, S. et al. Essential role of ubiquitin-specific protease 8 for receptor tyrosine kinase stability and endocytic trafficking in vivo. Mol. Cell Biol. 27, 5029–5039 (2007).
Haj, F. G., Verveer, P. J., Squire, A., Neel, B. G. & Bastiaens, P. I. Imaging sites of receptor dephosphorylation by PTP1B on the surface of the endoplasmic reticulum. Science 295, 1708–1711 (2002).
Eden, E. R., White, I. J., Tsapara, A. & Futter, C. E. Membrane contacts between endosomes and ER provide sites for PTP1B-epidermal growth factor receptor interaction. Nature Cell Biol. 12, 267–272 (2010). Shows that the EGFR–PTP1B interaction occurs at sites of direct contact between the perimeter membrane of multivesicular bodies and the ER. This population of EGFR undergoes ESCRT- mediated sorting within MVBs, and PTP1B activity promotes EGFR sequestration into internal vesicles of the MVB.
Stuible, M. et al. PTP1B targets the endosomal sorting machinery: dephosphorylation of regulatory sites on the endosomal sorting complex required for transport component STAM2. J. Biol. Chem. 285, 23899–23907 (2010).
Mattila, E. et al. Negative regulation of EGFR signalling through integrin-α1β1-mediated activation of protein tyrosine phosphatase TCPTP. Nature Cell Biol. 7, 78–85 (2005).
Xu, Y., Tan, L. J., Grachtchouk, V., Voorhees, J. J. & Fisher, G. J. Receptor-type protein-tyrosine phosphatase-κ regulates epidermal growth factor receptor function. J. Biol. Chem. 280, 42694–42700 (2005).
Berset, T. A., Hoier, E. F. & Hajnal, A. The C. elegans homolog of the mammalian tumor suppressor Dep-1/Scc1 inhibits EGFR signaling to regulate binary cell fate decisions. Genes Dev. 19, 1328–1340 (2005).
Tarcic, G. et al. An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase controlling EGFR endocytosis. Curr. Biol. 19, 1788–1798 (2009).
Ruivenkamp, C. A. et al. Ptprj is a candidate for the mouse colon-cancer susceptibility locus Scc1 and is frequently deleted in human cancers. Nature Genet. 31, 295–300 (2002).
Hoepfner, S. et al. Modulation of receptor recycling and degradation by the endosomal kinesin KIF16B. Cell 121, 437–50 (2005).
Carlucci, A. et al. PTPD1 supports receptor stability and mitogenic signaling in bladder cancer cells. J. Biol. Chem. 285, 39260–39270 (2010).
Prenzel, N. et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402, 884–888 (1999).
Biscardi, J. S. et al. c-Src-mediated phosphorylation of the epidermal growth factor receptor on Tyr845 and Tyr1101 is associated with modulation of receptor function. J. Biol. Chem. 274, 8335–8343 (1999).
Zwang, Y. & Yarden, Y. p38 MAP kinase mediates stress-induced internalization of EGFR: implications for cancer chemotherapy. EMBO J. 25, 4195–4206 (2006).
Zimmermann, S. & Moelling, K. Phosphorylation and regulation of Raf by Akt (protein kinase B). Science 286, 1741–1744 (1999).
Dhillon, A. S., Meikle, S., Yazici, Z., Eulitz, M. & Kolch, W. Regulation of Raf-1 activation and signalling by dephosphorylation. EMBO J. 21, 64–71 (2002).
Dougherty, M. K. et al. Regulation of Raf-1 by direct feedback phosphorylation. Mol. Cell 17, 215–224 (2005).
Cloughesy, T. F. et al. Antitumor activity of rapamycin in a Phase I trial for patients with recurrent PTEN-deficient glioblastoma. PLoS Med. 5, e8 (2008). Results of a Phase I clinical trial of rapamycin, an inhibitor of mTOR, in patients with recurrent glioblastoma. Rapamycin treatment led to AKT activation in seven out of 14 patients, presumably owing to loss of negative feedback.
Bartel, D. P. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 116, 281–297 (2004).
Li, X. & Carthew, R. W. A microRNA mediates EGF receptor signaling and promotes photoreceptor differentiation in the Drosophila eye. Cell 123, 1267–1277 (2005).
Davis, B. N., Hilyard, A. C., Lagna, G. & Hata, A. SMAD proteins control DROSHA-mediated microRNA maturation. Nature 454, 56–61 (2008).
Avraham, R. et al. EGF decreases the abundance of microRNAs that restrain oncogenic transcription factors. Sci. Signal. 3, ra43 (2010). Reported EGF-induced rapid turnover of a group of microRNAs, termed ID-miRs, which regulate transcription of oncogenic transcription factors.
Herschman, H. R. Primary response genes induced by growth factors and tumor promoters. Annu. Rev. Biochem. 60, 281–319 (1991).
Amit, I. et al. A module of negative feedback regulators defines growth factor signaling. Nature Genet. 39, 503–512 (2007). Uncovered transcription-dependent feedback loops, which inactivate the early response genes which are collectively upregulated in response to growth factors.
Lau, L. F. & Nathans, D. Expression of a set of growth-related immediate early genes in BALB/c 3T3 cells: coordinate regulation with c-fos or c-myc. Proc. Natl Acad. Sci. USA 84, 1182–1186 (1987).
Hargreaves, D. C., Horng, T. & Medzhitov, R. Control of inducible gene expression by signal-dependent transcriptional elongation. Cell 138, 129–145 (2009).
Fujita, T., Piuz, I. & Schlegel, W. Negative elongation factor NELF controls transcription of immediate early genes in a stimulus-specific manner. Exp. Cell Res. 315, 274–284 (2009).
Ramirez-Carrozzi, V. R. et al. A unifying model for the selective regulation of inducible transcription by CpG islands and nucleosome remodeling. Cell 138, 114–128 (2009).
Wang, Z. et al. Genome-wide mapping of HATs and HDACs reveals distinct functions in active and inactive genes. Cell 138, 1019–1031 (2009). References 65–68 demonstrated permissive structures of the promoters of IEGs, which enable rapid induction of transcription, and also uncovered novel mechanisms that suppress IEG expression at the basal state.
Bluthgen, N. et al. A systems biological approach suggests that transcriptional feedback regulation by dual-specificity phosphatase 6 shapes extracellular signal-related kinase activity in RAS-transformed fibroblasts. FEBS J. 276, 1024–1035 (2009).
Carballo, E., Lai, W. S. & Blackshear, P. J. Feedback inhibition of macrophage tumor necrosis factor-α production by tristetraprolin. Science 281, 1001–1005 (1998).
Jing, Q. et al. Involvement of microRNA in AU-rich element-mediated mRNA instability. Cell 120, 623–634 (2005).
Yilmaz, M. & Christofori, G. EMT, the cytoskeleton, and cancer cell invasion. Cancer Metastasis Rev. 28, 15–33 (2009).
Nieman, M. T., Prudoff, R. S., Johnson, K. R. & Wheelock, M. J. N-cadherin promotes motility in human breast cancer cells regardless of their E-cadherin expression. J. Cell Biol. 147, 631–644 (1999).
Katz, M. et al. A reciprocal tensin-3-cten switch mediates EGF-driven mammary cell migration. Nature Cell Biol. 9, 961–969 (2007).
Sporn, M. B. & Todaro, G. J. Autocrine secretion and malignant transformation of cells. N. Engl. J. Med. 303, 878–880 (1980).
Joslin, E. J., Opresko, L. K., Wells, A., Wiley, H. S. & Lauffenburger, D. A. EGF-receptor-mediated mammary epithelial cell migration is driven by sustained ERK signaling from autocrine stimulation. J. Cell Sci. 120, 3688–3699 (2007).
Goswami, S. et al. Macrophages promote the invasion of breast carcinoma cells via a colony-stimulating factor-1/epidermal growth factor paracrine loop. Cancer Res. 65, 5278–5283 (2005).
Janes, K. A. et al. The response of human epithelial cells to TNF involves an inducible autocrine cascade. Cell 124, 1225–1239 (2006). Shows that challenging cells with multiple extracellular signals induces an autocrine cascade involving the release of, and response to, additional, newly secreted factors.
Sheng, Q. et al. An activated ErbB3/NRG1 autocrine loop supports in vivo proliferation in ovarian cancer cells. Cancer Cell 17, 298–310 (2010).
Khambata-Ford, S. et al. Expression of epiregulin and amphiregulin and K-ras mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J. Clin. Oncol. 25, 3230–3237 (2007).
Alon, U. Network motifs: theory and experimental approaches. Nature Rev. Genet. 8, 450–461 (2007).
Bruggeman, F. J., Westerhoff, H. V., Hoek, J. B. & Kholodenko, B. N. Modular response analysis of cellular regulatory networks. J. Theor. Biol. 218, 507–520 (2002).
Marshall, C. J. Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation. Cell 80, 179–185 (1995).
Heasley, L. E. & Johnson, G. L. The β-PDGF receptor induces neuronal differentiation of PC12 cells. Mol. Biol. Cell 3, 545–553 (1992).
Nagashima, T. et al. Quantitative transcriptional control of ErbB receptor signaling undergoes graded to biphasic response for cell differentiation. J. Biol. Chem. 282, 4045–4056 (2007).
Santos, S. D., Verveer, P. J. & Bastiaens, P. I. Growth factor-induced MAPK network topology shapes Erk response determining PC-12 cell fate. Nature Cell Biol. 9, 324–330 (2007). Modular-response analysis was applied to PC-12 cells activated with EGF or NGF. On EGF stimulation, the network exhibited negative feedback, whereas a positive feedback was observed on NGF stimulation.
Murphy, L. O., Smith, S., Chen, R. H., Fingar, D. C. & Blenis, J. Molecular interpretation of ERK signal duration by immediate early gene products. Nature Cell Biol. 4, 556–564 (2002).
Sasagawa, S., Ozaki, Y., Fujita, K. & Kuroda, S. Prediction and validation of the distinct dynamics of transient and sustained ERK activation. Nature Cell Biol. 7, 365–373 (2005).
von Kriegsheim, A. et al. Cell fate decisions are specified by the dynamic ERK interactome. Nature Cell Biol. 11, 1458–1464 (2009). Using proteomics and GF-stimulated PC-12 cells, this report identified 60 proteins that changed their binding to ERK during differentiation, including effectors of signal duration, ERK localization and crosstalk with the AKT pathway.
Shankaran, H., Wiley, H. S. & Resat, H. Receptor downregulation and desensitization enhance the information processing ability of signalling receptors. BMC Syst. Biol. 1, 48 (2007).
Aquino, G. & Endres, R. G. Increased accuracy of ligand sensing by receptor internalization. Phys. Rev. E Stat. Nonlin. Soft Matter Phys. 81, 021909 (2010).
Yeung, K. et al. Suppression of Raf-1 kinase activity and MAP kinase signalling by RKIP. Nature 401, 173–177 (1999).
Corbit, K. C. et al. Activation of Raf-1 signaling by protein kinase C through a mechanism involving Raf kinase inhibitory protein. J. Biol. Chem. 278, 13061–13068 (2003).
Bhalla, U. S., Ram, P. T. & Iyengar, R. MAP kinase phosphatase as a locus of flexibility in a mitogen-activated protein kinase signaling network. Science 297, 1018–1023 (2002).
Lahav, G. et al. Dynamics of the p53-Mdm2 feedback loop in individual cells. Nature Genet. 36, 147–150 (2004).
Kholodenko, B. N. Negative feedback and ultrasensitivity can bring about oscillations in the mitogen-activated protein kinase cascades. Eur. J. Biochem. 267, 1583–1588 (2000).
Dong, C., Waters, S. B., Holt, K. H. & Pessin, J. E. SOS phosphorylation and disassociation of the Grb2-SOS complex by the ERK and JNK signaling pathways. J. Biol. Chem. 271, 6328–6332 (1996).
Waters, S. B. et al. Insulin and epidermal growth factor receptors regulate distinct pools of Grb2-SOS in the control of Ras activation. J. Biol. Chem. 271, 18224–18230 (1996).
Shin, S. Y. et al. Positive- and negative-feedback regulations coordinate the dynamic behavior of the Ras-Raf-MEK-ERK signal transduction pathway. J. Cell Sci. 122, 425–435 (2009).
Shankaran, H. et al. Rapid and sustained nuclear-cytoplasmic ERK oscillations induced by epidermal growth factor. Mol. Syst. Biol. 5, 332 (2009).
Cohen-Saidon, C., Cohen, A. A., Sigal, A., Liron, Y. & Alon, U. Dynamics and variability of ERK2 response to EGF in individual living cells. Mol. Cell 36, 885–893 (2009). References 99–101 observed oscillatory nucleo- cytoplasmic translocations of ERK in EGF-treated cells, and combined the data with mathematical models. A fold-change response, along with negative-feedback loops (for example, from ERK to SOS) and other mechanisms were found to have crucial roles in generating oscillatory behaviour.
Ashall, L. et al. Pulsatile stimulation determines timing and specificity of NF-κB-dependent transcription. Science 324, 242–246 (2009).
Barabasi, A. L. & Oltvai, Z. N. Network biology: understanding the cell's functional organization. Nature Rev. Genet. 5, 101–113 (2004).
Behar, M., Hao, N., Dohlman, H. G. & Elston, T. C. Mathematical and computational analysis of adaptation via feedback inhibition in signal transduction pathways. Biophys. J. 93, 806–821 (2007).
Ma, W., Trusina, A., El-Samad, H., Lim, W. A. & Tang, C. Defining network topologies that can achieve biochemical adaptation. Cell 138, 760–773 (2009). The authors searched all possible three-node enzyme topologies to identify those that could perform adaptation. Only two core topologies emerged: a negative-feedback loop with a buffering node and an incoherent feedforward loop with a proportioner node.
Goentoro, L. & Kirschner, M. W. Evidence that fold-change, and not absolute level, of β-catenin dictates Wnt signaling. Mol. Cell 36, 872–884 (2009).
Ekstrand, A. J. et al. Genes for epidermal growth factor receptor, transforming growth factor α, and epidermal growth factor and their expression in human gliomas in vivo. Cancer Res. 51, 2164–2172 (1991).
Slamon, D. J. et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244, 707–712 (1989).
Prickett, T. D. et al. Analysis of the tyrosine kinome in melanoma reveals recurrent mutations in ERBB4. Nature Genet. 41, 1127–1132 (2009).
Lynch, T. J. et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N. Engl. J. Med. 350, 2129–2139 (2004).
Shtiegman, K. et al. Defective ubiquitinylation of EGFR mutants of lung cancer confers prolonged signaling. Oncogene 26, 6968–6978 (2007).
Tzahar, E. et al. Pathogenic poxviruses reveal viral strategies to exploit the ErbB signaling network. EMBO J. 17, 5948–5963 (1998).
Reddy, C. C., Niyogi, S. K., Wells, A., Wiley, H. S. & Lauffenburger, D. A. Engineering epidermal growth factor for enhanced mitogenic potency. Nature Biotech. 14, 1696–1699 (1996).
Schulze, A., Lehmann, K., Jefferies, H. B., McMahon, M. & Downward, J. Analysis of the transcriptional program induced by Raf in epithelial cells. Genes Dev. 15, 981–994 (2001).
Barozzi, C. et al. Relevance of biologic markers in colorectal carcinoma: a comparative study of a broad panel. Cancer 94, 647–657 (2002).
Yi, W. et al. Expression of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins in human ependymoma relates to tumor location, WHO grade, and patient age. Clin. Neuropathol. 28, 21–27 (2009).
Ying, H. et al. Mig-6 controls EGFR trafficking and suppresses gliomagenesis. Proc. Natl Acad. Sci. USA 107, 6912–6917 (2010).
Sargin, B. et al. Flt3-dependent transformation by inactivating c-Cbl mutations in AML. Blood 110, 1004–1012 (2007).
Rao, D. S. et al. Huntingtin-interacting protein 1 is overexpressed in prostate and colon cancer and is critical for cellular survival. J. Clin. Invest. 110, 351–360 (2002).
Goentoro, L. A. et al. Quantifying the Gurken morphogen gradient in Drosophila oogenesis. Dev. Cell 11, 263–272 (2006).
Yeger-Lotem, E. et al. Network motifs in integrated cellular networks of transcription-regulation and protein-protein interaction. Proc. Natl Acad. Sci. USA 101, 5934–5939 (2004).
French, A. R., Sudlow, G. P., Wiley, H. S. & Lauffenburger, D. A. Postendocytic trafficking of epidermal growth factor-receptor complexes is mediated through saturable and specific endosomal interactions. J. Biol. Chem. 269, 15749–15755 (1994).
Traverse, S. et al. EGF triggers neuronal differentiation of PC12 cells that overexpress the EGF receptor. Curr. Biol. 4, 694–701 (1994).
We thank R. Milo and members of our laboratory for comments. Our laboratory is supported by research grants from the National Cancer Institute, the Seventh Framework Program (FP7) of the European Commission, the German Research Foundation (DFG), M. Adelson and S. G. Adelson of the Medical Research Foundation, the Kekst Family Institute for Medical Genetics, the Kirk Center for Childhood Cancer and Immunological Disorders, the Women's Health Research Center funded by Bennett-Pritzker Endowment Fund, the Marvelle Koffler Program for Breast Cancer Research and the M.D. Moross Institute for Cancer Research. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair.
The authors declare no competing financial interests.
- Extracellular signal-related kinase pathway
A three-tiered kinase module in which the first kinase, RAF, phosphorylates and activates the second kinase, mitogen-activated protein kinase kinase (MEK), which phosphorylates the third kinase, extracellular signal- regulated kinase (ERK), in a two-step, non-processive reaction.
Concurrent partial loss of function of the protein product of duplicated genes, such that collaboration between respective gene products reconstitutes the full set of sub-functions attributed to the original ancestor.
Coexistence of functionally similar components offering an alternative route for signal propagation if one of the components is inactivated.
- Feedback loop
A composite two-arm loop in which a protein, X, activates a downstream protein, Y, or transcriptionally induces a gene encoding Y. On activation, Y regulates X (positively or negatively).
The intake of material from the extracellular matrix or the membrane into vesicles that arise from the inward folding of the plasma membrane.
- Binary switching
When a system's output can transit between two states: 'on' and 'off', with (almost) no intermediate states.
- Analogue signal
A continuous signal that changes quantitatively in amplitude or concentration.
- E3 ubiquitin ligase
A protein that induces the attachment of ubiquitin, a small, highly conserved regulatory protein, to a Lys on a target protein and thus targets specific protein substrates for degradation.
- 14-3-3 chaperone
Adaptor/scaffold proteins that form homo- and heterodimers and bind, through specialized phosphorylated peptide motifs, to various proteins that are involved in signal transduction and in cell-cycle control.
- Immediate early genes
(IEGs). Genes that are induced rapidly and do not require new protein synthesis for their transcription.
- RNA polymerase II
(Pol II). An enzyme that catalyses the transcription of DNA to synthesize precursors of mRNA and most known small RNAs.
- Histone acetylation
Addition of an acetyl group to Lys amino acids on histone proteins, which renders DNA more accessible to transcription factors, and thus is linked to transcriptional activation.
- CpG island
A genomic region that contains a relatively high content of cytosine (C) and guanine (G) dinucleotides (the 'p' refers to the phosphodiester bond linking the two bases). CpG islands are found in many mammalian promoters and unlike scattered CpGs throughout the genome, which are usually hypermethylated, promoter CpG islands are normally hypomethylated.
- Epithelial–mesenchymal transition
(EMT). A phenotypic transformation of a highly polarized epithelial sheet of densely packed cells into sparse, motile cells resembling connective tissue cells. This transition involves a series of molecular switches, which are dependent on newly induced mRNAs and microRNAs.
A mode in which it is easier to maintain the system in its 'on' state than to toggle the system between 'on' and 'off'.
- Network motifs
A pattern of interactions that recurs in cellular networks significantly more often than in randomized networks.
An adrenal gland tumour that originates from neural crest cells.
- Feedforward loop
A regulatory pattern in which a stimulus (X) feeds into a response (Y) via more than one route: directly into Y or indirectly via Z (which interacts with Y). In a coherent feedforward loop the sign of the leg from X to Y equals the summation of the alternative leg (X-to-Z-to-Y). In any other case, the design is referred to as an incoherent feedforward loop.
- Scale-free network
A non-uniform network whose connectivity (the number of edges of each of the nodes) follows a power law. Scale-free biological networks are mostly comprised of nodes with one to two edges, and several highly linked hubs with six or more edges.
- Network hubs
Richly linked nodes of the network that account for most of the vulnerability of scale-free networks, as damage to one of the hubs of a network can break it up into segregated sub-graphs.
About this article
Cite this article
Avraham, R., Yarden, Y. Feedback regulation of EGFR signalling: decision making by early and delayed loops. Nat Rev Mol Cell Biol 12, 104–117 (2011). https://doi.org/10.1038/nrm3048
Excessive All-Trans Retinoic Acid Inhibits Cell Proliferation Through Upregulated MicroRNA-4680-3p in Cultured Human Palate Cells
Frontiers in Cell and Developmental Biology (2021)
N ‐glycosylated GPNMB ligand independently activates mutated EGFR signaling and promotes metastasis in NSCLC
Cancer Science (2021)
Engineered Nanotopography on the Microfibers of 3D-Printed PCL Scaffolds to Modulate Cellular Responses and Establish an In Vitro Tumor Model
ACS Applied Bio Materials (2021)
Nature Cell Biology (2021)
Briefings in Bioinformatics (2021)