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
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ABSTRACT 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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    • "Lrig proteins have large extracellular domains with either sixteen (Lrig1 and Lrig3) or fifteen (Lrig2) LRRs and three Ig domains (Fig. 1). Based on a distant similarity to Kekkons, which are the only large family of LRR-Ig proteins in flies [2], [3], Lrig proteins have been studied mostly as putative regulators of ErbB signaling pathways [4]–[6]. There are four ErbB receptors: ErbB1, which binds EGF and is thus better known as the EGF receptor (EGFR), and ErbB2-4, which bind Neuregulin (NRG) ligands [7]. "
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    ABSTRACT: The Lrig genes encode a family of transmembrane proteins that have been implicated in tumorigenesis, psoriasis, neural crest development, and complex tissue morphogenesis. Whether these diverse phenotypes reflect a single underlying cellular mechanism is not known. However, Lrig proteins contain evolutionarily conserved ectodomains harboring both leucine-rich repeats and immunoglobulin domains, suggesting an ability to bind to common partners. Previous studies revealed that Lrig1 binds to and inhibits members of the ErbB family of receptor tyrosine kinases by inducing receptor internalization and degradation. In addition, other receptor tyrosine kinase binding partners have been identified for both Lrig1 and Lrig3, leaving open the question of whether defective ErbB signaling is responsible for the observed mouse phenotypes. Here, we report that Lrig3, like Lrig1, is able to interact with ErbB receptors in vitro. We examined the in vivo significance of these interactions in the inner ear, where Lrig3 controls semicircular canal formation by determining the timing and extent of Netrin1 expression in the otic vesicle epithelium. We find that ErbB2 and ErbB3 are present in the early otic epithelium, and that Lrig3 acts cell-autonomously here, as would be predicted if Lrig3 regulates ErbB2/B3 activity. However, inhibition of ErbB activation in the chick otic vesicle has no detectable effect on Netrin gene expression or canal morphogenesis. Our results suggest that although both Lrig1 and Lrig3 can interact with ErbB receptors in vitro, modulation of Neuregulin signaling is unlikely to contribute to Lrig3-dependent processes of inner ear morphogenesis. These results highlight the similar binding properties of Lrig1 and Lrig3 and underscore the need to determine how these two family members bind to and regulate different receptors to affect diverse aspects of cell behavior in vivo.
    PLoS ONE 02/2010; 5(2):e8981. DOI:10.1371/journal.pone.0008981 · 3.23 Impact Factor
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