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GPCR-controlled membrane recruitment of negative regulator C2GAP1 locally inhibits Ras signaling for adaptation and long-range chemotaxis

Xu, X., Wen, X., Veltman, D. M., Keizer-Gunnink, I., Pots, H., Kortholt, A. & Jin, T., 21-Nov-2017, In : Proceedings of the National Academy of Sciences of the United States of America. 114, 47, p. 10092-10101 10 p.

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)10092-10101
Number of pages10
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number47
Early online date6-Nov-2017
Publication statusPublished - 21-Nov-2017

    Keywords

  • Journal Article, DICTYOSTELIUM-DISCOIDEUM, LEADING-EDGE, CELL-MOVEMENT, EUKARYOTIC CHEMOTAXIS, MEDIATED ACTIVATION, LIVING CELLS, CYCLIC-AMP, PROTEIN, TRANSDUCTION, RECEPTORS

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