Cyclic AMP signalling in Dictyostelium: G-proteins activate separate Ras pathways using specific RasGEFs.
In general, mammalian Ras guanine nucleotide exchange factors (RasGEFs) show little substrate specificity, although they are often thought to regulate specific pathways. Here, we provide in vitro and in vivo evidence that two RasGEFs can each act on specific Ras proteins. During Dictyostelium development, RasC and RasG are activated in response to cyclic AMP, with each regulating different downstream functions: RasG regulates chemotaxis and RasC is responsible for adenylyl cyclase activation. RasC activation was abolished in a gefA- mutant, whereas RasG activation was normal in this strain, indicating that RasGEFA activates RasC but not RasG. Conversely, RasC activation was normal in a gefR- mutant, whereas RasG activation was greatly reduced, indicating that RasGEFR activates RasG. These results were confirmed by the finding that RasGEFA and RasGEFR specifically released GDP from RasC and RasG, respectively, in vitro. This RasGEF target specificity provides a mechanism for one upstream signal to regulate two downstream processes using independent pathways.
Kae
Helmut
H
Department of Microbiology and Immunology, University of British Columbia, 3540-2350 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada.
Kortholt
Arjan
A
Rehmann
Holger
H
Insall
Robert H
RH
Van Haastert
Peter J M
PJ
Spiegelman
George B
GB
Weeks
Gerald
G
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism*; D004023:Dictyostelium / Q000235:genetics / Q000378:metabolism*; D019204:GTP-Binding Proteins / Q000378:metabolism*; D015800:Protozoan Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D020663:ras Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism*
D015800:Protozoan Proteins; D020663:ras Guanine Nucleotide Exchange Factors; C424065:rasG protein, Dictyostelium; D000242:Cyclic AMP; D019204:GTP-Binding Proteins