Drosophila PDZ-GEF, a guanine nucleotide exchange factor for Rap1 GTPase, reveals a novel upstream regulatory mechanism in the mitogen-activated protein kinase signaling pathway.
PDZ-GEF is a novel guanine nucleotide exchange factor for Rap1 GTPase. Here we isolated Drosophila melanogaster PDZ-GEF (dPDZ-GEF), which contains the all-conserved domains of mammalian and nematode PDZ-GEF including cyclic nucleotide monophosphate-binding, Ras exchange motif, PDZ, RA, and GEF domains. dPDZ-GEF loss-of-function mutants were defective in the development of various organs including eye, wing, and ovary. Many of these phenotypes are strikingly similar to the phenotype of the rolled mutant, implying that dPDZ-GEF functions upstream of the mitogen-activated protein (MAP) kinase pathway. Indeed, we found that dPDZ-GEF is specifically involved in photoreceptor cell differentiation, facilitating its neuronal fate via activation of the MAP kinase pathway. Rap1 was found to link dPDZ-GEF to the MAP kinase pathway; however, Ras was not involved in the regulation of the MAP kinase pathway by dPDZ-GEF and actually had an inhibitory function. The analyses of ovary development in dPDZ-GEF-deficient mutants also demonstrated another role of dPDZ-GEF independent of the MAP kinase signaling pathway. Collectively, our findings identify dPDZ-GEF as a novel upstream regulator of various morphogenetic pathways and demonstrate the presence of a novel, Ras-independent mechanism for activating the MAP kinase signaling pathway.
Lee
Jun Hee
JH
National Creative Research Initiatives Center for Cell Growth Regulation and Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Taejon 305-701, Korea.
Cho
Kyoung Sang
KS
Lee
Jihyun
J
Kim
Dohoon
D
Lee
Sung-Bae
SB
Yoo
Jungsik
J
Cha
Guang-Ho
GH
Chung
Jongkyeong
J
D000818:Animals; D017209:Apoptosis; D015152:Blotting, Northern; D019070:Cell Lineage; D002470:Cell Survival; D004331:Drosophila melanogaster; D005260:Female; D017930:Genes, Reporter; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism* / Q000502:physiology*; D006720:Homozygote; D020287:In Situ Nick-End Labeling; D020935:MAP Kinase Signaling System; D008297:Male; D008855:Microscopy, Electron, Scanning; D008957:Models, Genetic; D009419:Nerve Tissue Proteins; D010053:Ovary / Q000473:pathology; D010641:Phenotype; D017956:Photoreceptor Cells, Invertebrate / Q000378:metabolism / Q000648:ultrastructure; D011485:Protein Binding; D015398:Signal Transduction; D019076:Transgenes; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D020662:Guanine Nucleotide Exchange Factors; D009419:Nerve Tissue Proteins; C403525:RAPGEF2 protein, human; D020827:rap1 GTP-Binding Proteins