Tissue-specific functions of the Caenorhabditis elegans p120 Ras GTPase activating protein GAP-3.
All metazoan genomes encode multiple RAS GTPase activating proteins (RasGAPs) that negatively regulate the conserved RAS/MAPK signaling pathway. In mammals, several RasGAPs exhibit tumor suppressor activity by preventing excess RAS signal transduction. We have identified gap-3 as the to date missing Caenorhabditiselegans member of the p120 RasGAP family. By studying the genetic interaction of gap-3 with the two previously identified RasGAPs gap-1 and gap-2, we find that different combinations of RasGAPs are used to repress LET-60 RAS signaling depending on the cellular context. GAP-3 is the predominant negative regulator of RAS during meiotic progression of the germ cells, while GAP-1 is the key inhibitor of RAS during vulval induction. In other tissues such as the sex myoblasts or the chemosensory neurons, all three RasGAPs act in concert. The C. elegans RasGAPs have thus undergone partial specialization after gene duplication to allow the differential regulation of the RAS/MAPK signaling pathway in different cell types. A similar tissue specialization of the human tumor suppressor genes may explain the strong bias in the type of cancer they promote when mutated.
Stetak
Attila
A
Institute of Zoology, University of Zürich, Winterthurerstr. 190, CH-8057 Zürich, Switzerland.
Gutierrez
Peter
P
Hajnal
Alex
A
D000818:Animals; D019521:Body Patterning / Q000187:drug effects; D017173:Caenorhabditis elegans / Q000166:cytology / Q000196:embryology / Q000201:enzymology / Q000378:metabolism*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000378:metabolism*; D019070:Cell Lineage / Q000187:drug effects; D002630:Chemotactic Factors / Q000494:pharmacology; D002633:Chemotaxis / Q000187:drug effects; D005260:Female; D020690:GTPase-Activating Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D017930:Genes, Reporter; D005854:Germ Cells / Q000166:cytology / Q000187:drug effects; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D009928:Organ Specificity / Q000187:drug effects; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014158:Transcription, Genetic / Q000187:drug effects; D014835:Volatilization; D014844:Vulva / Q000187:drug effects / Q000196:embryology; D020729:p120 GTPase Activating Protein / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins / Q000378:metabolism; D018631:ras Proteins / Q000378:metabolism
D029742:Caenorhabditis elegans Proteins; D002630:Chemotactic Factors; C108739:GAP-1 protein, C elegans; D020690:GTPase-Activating Proteins; C533242:Gap-3 protein, C elegans; D020729:p120 GTPase Activating Protein; D020703:ras GTPase-Activating Proteins; C066646:let-60 protein, C elegans; D020794:Receptor Protein-Tyrosine Kinases; D018631:ras Proteins