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First published online August 25, 2005
doi: 10.1242/10.1242/dev.02006

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Regulating the dynamics of EGF receptor signaling in space and time

Department of Molecular Genetics, Weizmann Institute of Science, Rehovot 76100, Israel

View larger version (48K): [in a new window]   Fig. 1. Inducible negative regulators of EGFR signaling. Activation of the EGF receptor elicits the transcription of negative regulators, such as Argos, Kekkon and Sprouty, that restrict the range of signaling. EGFR activation usually leads to Argos and Kekkon induction, and in some settings also to the induction of Sprouty. Sprouty is also induced by, and inhibits, other signaling pathways, such as the FGF pathway. The cell expressing Rhomboid (RHO) and releasing cleaved Spitz (cSPI) is colored orange, the cell where prominent EGFR activation takes place is green, and the cell where EGFR activation is repressed is red. (A) Argos is induced only in the cells receiving the highest levels of the EGFR signal cSPI, i.e. those closest to the source of ligand processing. Argos is secreted from the cells where it is produced and associates with cSPI, thus restricting the levels of cSPI molecules that diffuse beyond the expression domain of Argos. Because Argos associates with cSPI, the actual range of Argos diffusion is not crucial for its long-range inhibitory effect. (B) Sprouty is induced in the cells receiving high and intermediate levels of EGFR activation. Following its production, Sprouty undergoes tyrosine phosphorylation, which is induced by the activated receptor, to produce a potent inhibitor. (C) Kekkon is induced in the cells receiving high and intermediate levels of EGFR activation. The protein localizes to the plasma membrane, where it forms heterodimers with EGFR.

View larger version (42K): [in a new window]   Fig. 2. Different modes of EGFR signaling. Although the same canonical EGFR signaling pathway is used in numerous developmental settings, subtle alterations in its regulatory circuitry lead to distinct modes of signaling. (A) A single signaling burst. In this mode, ligand processing is confined to the cells expressing rhomboid (RHO, orange). Secreted ligand is presented to neighboring cells, and the induction of negative-feedback loops (red) confines the signaling zone (green). This is the simplest, and most commonly used, EGFR signaling mode. The figure depicts EGFR signaling in the Drosophila embryonic ventral ectoderm, where rho is expressed in the midline glial cells. (B) Multiple activation cycles from a fixed source. Induction of Argos expression in the cells immediately adjacent to the cleaved ligand source limits the range of activation. Once these cells delaminate, the signal from the original source can now reach the next ring of cells, giving rise to a cyclic pattern of EGFR activation. This mode was first described in the induction of embryonic oenocyte cell fates. (C) Multiple activation cycles from an expanding source. This mode operates during the development of the Drosophila eye, and relies on the expansion of rho expression. A different cell type is induced following each round of EGFR activation, by combining EGFR signaling with distinct transcriptional cues that are unique to each cell type. Each burst of EGFR activation has to be discrete in space and time. (D) The relay of signal source. When signaling takes place between two cell types, rho induction in the cells where EGFR is activated converts them to a signaling source. This response leads to amplification of the original signal, and extends signaling over time, even after the original signal source can no longer be detected. This type of signaling occurs during Drosophila oogenesis, and in C. elegans during vulval cell fate induction. The figure shows a Drosophila egg chamber, where Gurken signal emanating from the oocyte leads to EGFR activation in the follicle cells. The convergence of EGFR and BMP (DPP) signaling from the stretch follicle cells induces rho expression in the dorsal anterior follicle cells, which generates cleaved Spitz in these cells to amplify the signal. Anteroposterior (AP) and dorsoventral (DV) axes are indicated.

View larger version (23K): [in a new window]   Fig. 3. Diverse interactions between EGFR and Notch signaling. (A) During the development of distinct cell types in the Drosophila eye, combined inputs from the EGFR pathway (through Pointed) and the Notch (N) pathway [through SU(H)], in conjunction with distinct transcription factors, induce the relevant target genes. For example, the two pathways in conjunction with Lozenge (LZ), induce Drosophila Pax2 (shaven - FlyBase) expression in the future cone cells. (B) The combined activities of EGFR and Notch signaling integrated in a `feed-forward' loop. EGFR activation in the Drosophila photoreceptor (R) cells induces Delta (DL) expression. The combination of the Spitz and DL ligands presented by the R cells induces the cone cell fate, by triggering target gene expression, such as that of Drosophila Pax2. N pathway activation is marked by an open arrow. (C) Mutual repression between the EGFR and Notch pathways refines cell fates during C. elegans vulval development. The anchor cell provides the EGFR ligand (LIN-3) to the primary vulval precursor cell (VPC, green). EGFR signaling in this cell leads to DSL expression (a Notch ligand) and reduces the capacity of the cell to respond to N activation. This cell displays DSL to the secondary VPCs. N signaling in these cells triggers repressors of EGFR signaling (red), thus eliminating their responses to lower levels of the EGFR ligand presented by the anchor cell. In parallel, EGFR activation represses the expression of the receptor tyrosine phosphatase DEP-1 in the primary VPC, whereas a Notch-independent mechanism induces DEP-1 expression in the secondary VPCs. (D) A similar circuit of mutual repression during the determination of vein versus inter-vein fates in the Drosophila wing. Restricted expression of rhomboid only in the future vein cells leads to localized, autocrine EGFR activation (green) and induction of DL expression. EGFR signaling also reinforces the expression of rhomboid. In parallel, MAPK activation by EGFR in these cells can phosphorylate and attenuate the activity of Groucho, which is involved in executing the transcriptional repression responses elicited by N signaling. EGFR activation also eliminates the HMG-box transcriptional repressor Capicua (CIC). In the adjacent inter-vein cells, rhomboid expression is repressed by N signaling, and CIC represses other vein-specific genes. Thus, EGFR signaling is confined to the veins, whereas N signaling is restricted to the intervein cells.