G-protein coupled receptors
Final Report Abstract
"Dictyostelium discoideum" harbors a surprisingly large number of G protein coupled receptors (GPCRs). This includes members of families found in metazoa but also representatives of GPCR families unique to lower eukaryotes. Proteins belonging to two different families have been chosen for our investigation, GPHR and RpkA which are both cytoplasmic proteins. GPHR (GPR89) homologs have been found in plants and in mammals, RpkA is a member of a unique class of GPCRs, the GPCR-PIPKs, which carry a phosphatidylinositol phosphate kinase (PIPK) domain at their C-terminus and thus can directly activate downstream phospholipid signaling. GPCR-PIPKs are now described as GPCR-bigrams. These are proteins in which a typical signaling domain is preceded by a GPCR domain. RpkA is present on phagosomes and a subpopulation of vesicles positive for endosomal and lysosomal markers. Loss of RpkA leads to a phagocytosis defect and results in an enhanced survival of the pathogenic bacterium "L. pneumophila" which could originate from the observed reduced phosphoinositide turnover and/or a reduced autophagy. RpkA is thus a component of the defense system of "D. discoideum". For GPHR diverse roles have been proposed. In plants it was described as abscisic acid receptor, in mammalian cells it is thought to act as Golgi pH regulator. Complete loss of the protein in mice is lethal, a tissue-specific knockout in skin is associated with a skin barrier defect. We showed that in "D. discoideum" GPHR is present on membranes of the ER, the Golgi apparatus, and on lysosomal and endosomal membranes. Loss of GPHR caused dysfunctioning of processes related to internal membrane flow such as secretion and phagocytosis. A search for interacting proteins led to the identification of a tripeptidyl peptidase 1 (TPP1F), a lysosomal enzyme. In man, mutations in the corresponding gene cause late infantile neuronal ceroid lipofuscinosis, a neurodegenerative disorder. Our finding of the TPP1-GPHR interaction may lead to new treatment options in the disease.
Publications
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(2013). A novel human receptor involved in bitter tastant detection identified using the model organism Dictyostelium discoideum. J. Cell Sci. 126, 5465-5476
Robery, Steven; Tyson, Richard; Dinh, Christopher; Kuspa, Adam; Noegel, Angelika A.; Bretschneider, Till; Andrews, Paul L. R. & Williams, Robin S. B.
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(2014). The Dictyostelium discoideum RACK1 orthologue has roles in growth and development. Cell Commun. Signal. 12:37
Omosigho, Napoleon Nosa; Swaminathan, Karthic; Plomann, Markus; Müller-Taubenberger, Annette; Noegel, Angelika A. & Riyahi, Tanja Y.
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(2014). The Genome of the Foraminiferan Reticulomyxa filosa. Curr. Biol. 24, 11–18
Glöckner, Gernot; Hülsmann, Norbert; Schleicher, Michael; Noegel, Angelika A.; Eichinger, Ludwig; Gallinger, Christoph; Pawlowski, Jan; Sierra, Roberto; Euteneuer, Ursula; Pillet, Loic; Moustafa, Ahmed; Platzer, Matthias; Groth, Marco; Szafranski, Karol & Schliwa, Manfred
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(2015). The Dictyostelium discoideum GPHR ortholog is an ER and Golgi protein with roles during development. Eukaryot. Cell 14, 41-54
Deckstein, Jaqueline; van Appeldorn, Jennifer; Tsangarides, Marios; Yiannakou, Kyriacos; Müller, Rolf; Stumpf, Maria; Sukumaran, Salil K.; Eichinger, Ludwig; Noegel, Angelika A. & Riyahi, Tanja Y.
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(2015). The Physarum polycephalum genome reveals extensive use of prokaryotic two-component and metazoan-type tyrosine kinase signaling. Genome Biol. Evol. 8, 109-125
Schaap, Pauline; Barrantes, Israel; Minx, Pat; Sasaki, Narie; Anderson, Roger W.; Bénard, Marianne; Biggar, Kyle K.; Buchler, Nicolas E.; Bundschuh, Ralf; Chen, Xiao; Fronick, Catrina; Fulton, Lucinda; Golderer, Georg; Jahn, Niels; Knoop, Volker; Landweber, Laura F.; Maric, Chrystelle; Miller, Dennis; Noegel, Angelika A.; ... & Marwan, Wolfgang
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(2017). A Tripeptidyl peptidase 1 is a binding partner of GPHR (Golgi pH regulator) in Dictyostelium. Disease Models & Mechanisms
Stumpf, Maria; Müller, Rolf; Gaßen, Berthold; Wehrstedt, Regina; Fey, Petra; Karow, Malte A.; Eichinger, Ludwig; Glöckner, Gernot & Noegel, Angelika A.
