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Xu, Xuehua, Wen, Xi, Veltman, DM Douwe M, Keizer-Gunnink, Ineke, Pots, Henderikus, Kortholt, Arjan, Jin, Tian, (2017) ' GPCR-controlled membrane recruitment of negative regulator C2GAP1 locally inhibits Ras signaling for adaptation and long-range chemotaxis. ' Proc. Natl. Acad. Sci. U.S.A.

 

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 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.
Status:	aheadofprint	Type:	Journal article	Source:	PUBMED	PubMed ID:	29109256

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	Genes addressed in this paper
	c2gapB	carA-1	carA-2	ngap	pkgB	rasC	rasG
Topics in this paper
Protein Functional Domain	X			X
Strains/Constructs		X	X	X		X	X
Cellular Location				X
Chemotaxis/Motility				X
Function/Process				X
Development/Morphogenesis				X
Signal Transduction		X	X	X	X	X	X
RNA Levels and Processing				X
Genome-wide Analysis	X
Genetic Interactions		X	X			X	X
Protein-Protein Interactions				X		X	X
Regulatory Role				X
Regulated By					X	X	X
Mutants/Phenotypes		X	X	X		X	X