PMID:12845332

Citation	Bivona, TG, Pérez De Castro, I, Ahearn, IM, Grana, TM, Chiu, VK, Lockyer, PJ, Cullen, PJ, Pellicer, A, Cox, AD and Philips, MR (2003) Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1. Nature 424:694-8
Abstract	Ras proteins regulate cellular growth and differentiation, and are mutated in 30% of cancers. We have shown recently that Ras is activated on and transmits signals from the Golgi apparatus as well as the plasma membrane but the mechanism of compartmentalized signalling was not determined. Here we show that, in response to Src-dependent activation of phospholipase Cgamma1, the Ras guanine nucleotide exchange factor RasGRP1 translocated to the Golgi where it activated Ras. Whereas Ca(2+) positively regulated Ras on the Golgi apparatus through RasGRP1, the same second messenger negatively regulated Ras on the plasma membrane by means of the Ras GTPase-activating protein CAPRI. Ras activation after T-cell receptor stimulation in Jurkat cells, rich in RasGRP1, was limited to the Golgi apparatus through the action of CAPRI, demonstrating unambiguously a physiological role for Ras on Golgi. Activation of Ras on Golgi also induced differentiation of PC12 cells, transformed fibroblasts and mediated radioresistance. Thus, activation of Ras on Golgi has important biological consequences and proceeds through a pathway distinct from the one that activates Ras on the plasma membrane.
Links	PubMed Online version:10.1038/nature01806
Keywords	Animals; COS Cells; Calcium/metabolism; Cell Differentiation; Cell Membrane/metabolism; DNA-Binding Proteins/metabolism; Enzyme Activation; Fibroblasts; Golgi Apparatus/metabolism; Guanine Nucleotide Exchange Factors; Humans; Intracellular Membranes/metabolism; Jurkat Cells; PC12 Cells; Phospholipase C gamma; Protein Transport; Proto-Oncogene Proteins pp60(c-src)/metabolism; Rats; Signal Transduction; Type C Phospholipases/metabolism; ras GTPase-Activating Proteins/metabolism; ras Proteins/metabolism
edit table

Annotations

Gene product	Qualifier	GO Term	Evidence Code	with/from	Aspect	Extension	Notes	Status
HUMAN:GRP1		GO:0090630: activation of GTPase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Fig 3e; overexpression of RasGRP1 was induced to determine the protein's normal function	complete CACAO 2538
HUMAN:GRP1	involved_in	GO:0090630: activation of GTPase activity	ECO:0000315: mutant phenotype evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:RASL2	involved_in	GO:0034260: negative regulation of GTPase activity	ECO:0000314: direct assay evidence used in manual assertion		P		Seeded From UniProt	complete
HUMAN:RASL2		GO:0034261: negative regulation of Ras GTPase activity	ECO:0000314:		P		Fig 5b; over- and underexpression to determine role of CAPRI; directly blocks Ras activation	complete CACAO 2540

References

See Help:References for how to manage references in GONUTS.