|Abstract:Eukaryotic cells sense and migrate toward chemoattractant gradients using G protein-coupled receptor (GPCR) signaling pathways. The fascinating feature of chemotaxis is that cells migrate through chemoattractant gradients with huge concentration ranges by "adaptation." Adaptive cells no longer respond to the present stimulus but remain sensitive to stronger stimuli, providing the fundamental strategy for chemotaxis through gradients with a broad range of concentrations. Ras activation is the first step in the GPCR-mediated chemosensing signaling pathways that displays adaptation. However, the molecular mechanism of Ras adaptation is not fully understood. Here, we highlight C2GAP1, a GPCR-activated Ras negative regulator, that locally inhibits Ras signaling for adaptation and long-range chemotaxis in D. discoideum.