Phospholipase Cgamma activates Ras on the Golgi apparatus by means of RasGRP1.
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.
Bivona
Trever G
TG
Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, New York 10016, USA.
Pérez De Castro
Ignacio
I
Ahearn
Ian M
IM
Grana
Theresa M
TM
Chiu
Vi K
VK
Lockyer
Peter J
PJ
Cullen
Peter J
PJ
Pellicer
Angel
A
Cox
Adrienne D
AD
Philips
Mark R
MR
D000818:Animals; D019556:COS Cells; D002118:Calcium / Q000378:metabolism; D002454:Cell Differentiation; D002462:Cell Membrane / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004789:Enzyme Activation; D005347:Fibroblasts; D006056:Golgi Apparatus / Q000378:metabolism*; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D019169:Jurkat Cells; D016716:PC12 Cells; D051966:Phospholipase C gamma; D021381:Protein Transport; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; C491144:RASA4 protein, human; C491790:RASGRP1 protein, human; C491789:Rasgrp1 protein, rat; D020703:ras GTPase-Activating Proteins; D016392:Proto-Oncogene Proteins pp60(c-src); D010738:Type C Phospholipases; D051966:Phospholipase C gamma; D018631:ras Proteins; D002118:Calcium