GPCR-controlled membrane recruitment of negative regulator C2GAP1 locally inhibits Ras signaling for adaptation and long-range chemotaxis
| Autor: | Arjan Kortholt, Henderikus Pots, Tian Jin, Douwe M. Veltman, Xuehua Xu, Xi Wen, Ineke Keizer-Gunnink |
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| Přispěvatelé: | Cell Biochemistry |
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Cell Protozoan Proteins CYCLIC-AMP PROTEIN CELL-MOVEMENT TRANSDUCTION Dictyostelium discoideum 03 medical and health sciences Transduction (genetics) Cytosol Anti-apoptotic Ras signalling cascade Cyclic AMP medicine Journal Article Dictyostelium LIVING CELLS Actin G protein-coupled receptor Multidisciplinary biology Chemotaxis Cell Membrane GTPase-Activating Proteins DICTYOSTELIUM-DISCOIDEUM LEADING-EDGE EUKARYOTIC CHEMOTAXIS biology.organism_classification Adaptation Physiological Actins MEDIATED ACTIVATION Cell biology RECEPTORS Protein Transport 030104 developmental biology medicine.anatomical_structure Gene Expression Regulation PNAS Plus ras Proteins Signal Transduction |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America, 114(47), 10092-10101. NATL ACAD SCIENCES |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Eukaryotic cells chemotax in a wide range of chemoattractant concentration gradients, and thus need inhibitory processes that terminate cell responses to reach adaptation while maintaining sensitivity to higher-concentration stimuli. However, the molecular mechanisms underlying inhibitory processes are still poorly understood. Here, we reveal a locally controlled inhibitory process in a GPCR-mediated signaling network for chemotaxis in Dictyostelium discoideum We identified a negative regulator of Ras signaling, C2GAP1, which localizes at the leading edge of chemotaxing cells and is activated by and essential for GPCR-mediated Ras signaling. We show that both C2 and GAP domains are required for the membrane targeting of C2GAP1, and that GPCR-triggered Ras activation is necessary to recruit C2GAP1 from the cytosol and retains it on the membrane to locally inhibit Ras signaling. C2GAP1-deficient c2gapA(-) cells have altered Ras activation that results in impaired gradient sensing, excessive polymerization of F actin, and subsequent defective chemotaxis. Remarkably, these cellular defects of c2gapA(-) cells are chemoattractant concentration dependent. Thus, we have uncovered an inhibitory mechanism required for adaptation and long-range chemotaxis. |
| Databáze: | OpenAIRE |
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