Ghiglione C, Carraway III KL, Amundadottir LT, Boswell RE, Perrimon N, Duffy JBThe transmembrane molecule kekkon 1 acts in a feedback loop to negatively regulate the activity of the Drosophila EGF receptor during oogenesis. Cell 96: 847-856

Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Cell (Impact Factor: 32.24). 04/1999; 96(6):847-56. DOI: 10.1016/S0092-8674(00)80594-2
Source: PubMed


We have identified the Drosophila transmembrane molecule kekkon 1 (kek1) as an inhibitor of the epidermal growth factor receptor (EGFR) and demonstrate that it acts in a negative feedback loop to modulate the activity of the EGFR tyrosine kinase. During oogenesis, kek1 is expressed in response to the Gurken/EGFR signaling pathway, and loss of kek1 activity is associated with an increase in EGFR signaling. Consistent with our loss-of-function studies, we demonstrate that ectopic overexpression of kek1 mimics a loss of EGFR activity. We show that the extracellular and transmembrane domains of Kek1 can inhibit and physically associate with the EGFR, suggesting potential models for this inhibitory mechanism.

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Available from: Joseph Duffy, Dec 14, 2013
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    • "Later, Grk at the dorsal anterior corner of the oocyte activates EGFR signaling in overlying follicle cells and induces them to adopt a dorsal cell fate. After EGFR activation, the expression of several genes, such as argos (Zhao and Bownes, 1999), pointed (Morimoto et al., 1996), sprouty (Reich et al., 1999), and kekkon (Ghiglione et al., 1999), are upregulated, and these genes can be used as markers for dorsal follicle-cell differentiation and EGFR activity. To determine whether the mislocalization of Grk protein in Syx1A SH0113 germline clones resulted in defects in EGFR signaling and follicle-cell Fig. 1. "
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    ABSTRACT: Vesicle trafficking plays a crucial role in the establishment of cell polarity in various cellular contexts, including axis-pattern formation in the developing egg chamber of Drosophila. The EGFR ligand, Gurken (Grk), is first localized at the posterior of young oocytes for anterior-posterior axis formation and later in the dorsal-anterior region for induction of the dorsal-ventral (DV) axis, but regulation of Grk localization by membrane trafficking in the oocyte remains poorly understood. Here, we report that Syntaxin-1A (Syx1A) is required for efficient trafficking of Grk protein for DV patterning. We show that Syx1A is associated with the Golgi membrane and is required for the transportation of Grk-containing vesicles along the microtubules to their dorsal anterior destination in the oocyte. Our studies reveal that the Syx1A dependent trafficking of Grk protein is required for efficient EGFR signaling during DV patterning.
    Developmental Biology 11/2012; 373(2). DOI:10.1016/j.ydbio.2012.10.029 · 3.55 Impact Factor
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    • "Although both Lrig1 and Kekkon1 interact with the EGFR, their mechanisms of action differ substantially. The physical interaction of Kekkon1 with ErbB receptors interferes with ligand binding and receptor activation (Ghiglione et al. 1999, 2003). On the other hand, Lrig1 appears to restrict mammalian ErbB/EGF receptor signaling by enhancing Cbl (Casitas B-lineage lymphoma)-mediated receptor ubiquitination and degradation (Gur et al. 2004; Laederich et al. 2004). "
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    ABSTRACT: Neurotrophic growth factors control neuronal development by activating specific receptor tyrosine kinase positive signaling pathways, such as Ras-MAPK and PI3K-Akt cascades. Once activated, neurotrophic factor receptors also trigger a cascade of molecular events, named negative receptor signaling, that restricts the intensity of the positive signals and modulates cellular behavior. Thus, to avoid signaling errors that ultimately could lead to aberrant neuronal physiology and disease, negative signaling mechanisms have evolved to ensure that suitable thresholds of neuronal stimulation are achieved and maintained during right periods of time. Recent findings have revealed that neurotrophic factor receptor signaling is tightly modulated through the coordinated action of many different protein regulators that limit or potentiate signal propagation in spatially and temporally controlled manners, acting at specific points after receptor engagement. In this review, we discuss progress in this field, highlighting the importance of these modulators in axonal growth, guidance, neural connectivity, and nervous system regeneration.
    Journal of Neurochemistry 09/2012; 123(5). DOI:10.1111/jnc.12021 · 4.28 Impact Factor
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    • "The mechanism by which EGFR signaling represses pipe expression remains unclear. An important feature is that detectable EGFR signaling activity and pipe expression are not precisely complementary: at stage 10A of oogenesis, active phospho-MAPK and known EGFR targets are restricted to the dorsal ~30% of the follicular epithelium, whereas pipe expression spans the ventral ~40% region (Sen et al., 1998; Ghiglione et al., 1999; Peri et al., 1999; Reich et al., 1999; Jordan et al., 2000; Zhao et al., 2000). Accordingly, initial analyses suggested that pipe repression is not a direct consequence of EGFR signaling, but depends on longrange signals mediated by the homeodomain factor Mirror (Mirr) and the Notch-Fringe pathway (Jordan et al., 2000). "
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    ABSTRACT: Dorsoventral (DV) axis formation in Drosophila begins with selective activation of EGFR, a receptor tyrosine kinase (RTK), in dorsal-anterior (DA) ovarian follicle cells. A critical event regulated by EGFR signaling is the repression of the sulfotransferase-encoding gene pipe in dorsal follicle cells, but how this occurs remains unclear. Here we show that Mirror (Mirr), a homeodomain transcription factor induced by EGFR signaling in DA follicle cells, directly represses pipe expression by binding to a conserved element in the pipe regulatory region. In addition, we find that the HMG-box protein Capicua (Cic) supports pipe expression in ventral follicle cells by repressing Mirr in this region. Interestingly, this role of Cic resembles its function in regulating anteroposterior (AP) body patterning, where Cic supports gap gene expression in central regions of the embryo by repressing Tailless, a repressor induced by RTK signaling at the embryonic poles. Thus, related RTK-Cic repressor circuits regulate the early stages of Drosophila DV and AP body axis formation.
    Development 03/2012; 139(6):1110-4. DOI:10.1242/dev.076562 · 6.46 Impact Factor
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