Activation of the Drosophila C3G leads to cell fate changes and overproliferation during development, mediated by the RAS-MAPK pathway and RAP1.
The cellular signal transduction pathways by which C3G, a RAS family guanine nucleotide exchange factor, mediates v-crk transformation are not well understood. Here we report the identification of Drosophila C3G, which, like its human cognate, specifically binds to CRK but not DRK/GRB2 adaptor molecules. During Drosophila development, constitutive membrane binding of C3G, which also occurs during v-crk transformation, results in cell fate changes and overproliferation, mimicking overactivity of the RAS-MAPK pathway. The effects of C3G overactivity can be suppressed by reducing the gene dose of components of the RAS-MAPK pathway and of RAP1. These findings provide the first in vivo evidence that membrane localization of C3G can trigger activation of RAP1 and RAS resulting in the activation of MAPK, one of the hallmarks of v-crk transformation previously thought to be mediated through activation of SOS.
Ishimaru
S
S
Laboratory of Molecular Oncology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.
Williams
R
R
Clark
E
E
Hanafusa
H
H
Gaul
U
U
D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D001483:Base Sequence; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002455:Cell Division; D002874:Chromosome Mapping; D017931:DNA Primers / Q000235:genetics; D004330:Drosophila / Q000166:cytology / Q000254:growth & development* / Q000378:metabolism*; D005123:Eye / Q000254:growth & development / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D020662:Guanine Nucleotide Exchange Factors; D006801:Humans; D019476:Insect Proteins / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D050736:Oncogene Protein v-crk; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D015398:Signal Transduction; D014921:Wings, Animal / Q000254:growth & development / Q000378:metabolism; D020668:rap GTP-Binding Proteins; D020663:ras Guanine Nucleotide Exchange Factors; D018631:ras Proteins / Q000378:metabolism*
D017931:DNA Primers; D020662:Guanine Nucleotide Exchange Factors; D019476:Insect Proteins; D050736:Oncogene Protein v-crk; D011506:Proteins; D015682:Retroviridae Proteins, Oncogenic; D020663:ras Guanine Nucleotide Exchange Factors; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019204:GTP-Binding Proteins; D020668:rap GTP-Binding Proteins; D018631:ras Proteins