Mechanism of inhibition of theDrosophilaand mammalian EGF receptors by the transmembrane protein Kekkon 1

Autor: Norbert Perrimon, Margret B. Andresdottir, Laufey T. Amundadottir, Stéphane Noselli, David Bilder, John A. Diamonti, Kermit L. Carraway, Christian Ghiglione
Přispěvatelé: Institut de signalisation, biologie du développement et cancer (ISBDC), Centre National de la Recherche Scientifique (CNRS)-Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA), Dept of Genetics, Harvard Medical School, Harvard Medical School [Boston] (HMS), Division of Cancer Genetics, Reykjavík University, Department of Molecular & Cell Biology [Berkeley], University of California [Berkeley], University of California-University of California, Division of Signal Transduction, Beth Israel Deaconess Medical Center [Boston] (BIDMC), Harvard Medical School [Boston] (HMS)-Harvard Medical School [Boston] (HMS), Davis Cancer Center, University of California [Davis] (UC Davis)
Rok vydání: 2003
Předmět:
MESH: Signal Transduction
MESH: Epidermal Growth Factor
medicine.medical_treatment
Animals
Genetically Modified
Mice
MESH: Protein Structure
Tertiary
ErbB Receptors
Drosophila Proteins
Wings
Animal
MESH: Animals
Epidermal growth factor receptor
Receptor
[SDV.BDD]Life Sciences [q-bio]/Development Biology
Feedback
Physiological
MESH: Photoreceptors
Invertebrate
biology
Transmembrane protein
Cell biology
Transmembrane domain
Drosophila melanogaster
Female
Photoreceptor Cells
Invertebrate
MESH: Membrane Proteins
Protein Binding
Signal Transduction
MESH: Drosophila Proteins
Embryonic Structures
MESH: Protein Tyrosine Phosphatases
MESH: Receptor
Epidermal Growth Factor
MESH: Embryonic Structures
Cell Line
MESH: Drosophila melanogaster
MESH: Animals
Genetically Modified
ErbB
medicine
Animals
Humans
MESH: Protein Binding
MESH: Mice
Molecular Biology
MESH: Humans
Epidermal Growth Factor
MESH: Feedback
Biochemical
Growth factor
Membrane Proteins
MESH: Wing
Fusion protein
Protein Structure
Tertiary
MESH: Cell Line
biology.protein
Protein Tyrosine Phosphatases
MESH: Female
Developmental Biology
Zdroj: Development (Cambridge, England)
Development (Cambridge, England), Company of Biologists, 2003, 130 (18), pp.4483-93
ISSN: 1477-9129
0950-1991
DOI: 10.1242/dev.00617
Popis: The transmembrane protein Kekkon 1 (Kek1) has previously been shown to act in a negative feedback loop to downregulate the Drosophila Epidermal Growth Factor Receptor (DER) during oogenesis. We show that this protein plays a similar role in other DER-mediated developmental processes. Structure-function analysis reveals that the extracellular Leucine-Rich Repeat(LRR) domains of Kek1 are critical for its function through direct association with DER, whereas its cytoplasmic domain is required for apical subcellular localization. In addition, the use of chimeric proteins between Kek1 extracellular and transmembrane domains fused to DER intracellular domain indicates that Kek1 forms an heterodimer with DER in vivo. To characterize more precisely the mechanism underlying the Kek1/DER interaction, we used mammalian ErbB/EGFR cell-based assays. We show that Kek1 is capable of physically interacting with each of the known members of the mammalian ErbB receptor family and that the Kek1/EGFR interaction inhibits growth factor binding, receptor autophosphorylation and Erk1/2 activation in response to EGF. Finally, in vivo experiments show that Kek1 expression potently suppresses the growth of mouse mammary tumor cells derived from aberrant ErbB receptors activation, but does not interfere with the growth of tumor cells derived from activated Ras. Our results underscore the possibility that Kek1 may be used experimentally to inhibit ErbB receptors and point to the possibility that, as yet uncharacterized, mammalian transmembrane LRR proteins might act as modulators of growth factor signalling.
Databáze: OpenAIRE
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