GPCR-controlled membrane recruitment of negative regulator C2GAP1 locally inhibits Ras signaling for adaptation and long-range chemotaxis
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol.114, no.47, 2017 (SCI-Expanded, Scopus)
- Publication Type: Article / Article
- Volume: 114 Issue: 47
- Publication Date: 2017
- Doi Number: 10.1073/pnas.1703208114
- Journal Name: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
- Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
- Keywords: chemotaxis, adaptation, G protein-coupled receptor, Ras activation, Ras GAP, DICTYOSTELIUM-DISCOIDEUM, LEADING-EDGE, CELL-MOVEMENT, EUKARYOTIC CHEMOTAXIS, MEDIATED ACTIVATION, LIVING CELLS, CYCLIC-AMP, PROTEIN, TRANSDUCTION, RECEPTORS
- Süleyman Demirel University Affiliated: No
Abstract
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 Dictyoste-lium 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.