Evidence that dynamin-2 functions as a signal-transducing GTPase.
The role of dynamin GTPases in the regulation of receptor-mediated endocytosis is well established. Here, we present new evidence that the ubiquitously expressed isoform dynamin-2 (dyn2) can also function in a signal transduction pathway(s). A </=5-fold increase of dyn2 relative to endogenous levels activates the transcription factor p53 and induces apoptosis, as demonstrated by reduced cell proliferation, DNA fragmentation, and caspase-3 activation. Dyn2-triggered apoptosis occurs only in dividing cells and is p53 dependent. A mutant defective in GTP binding does not trigger apoptosis, indicating that increased levels of dyn2.GTP, rather than protein levels per se, are required to transduce signals that activate p53. A truncated dyn2 lacking the COOH-terminal proline/arginine-rich domain (PRD), which interacts with many SH3 domain-containing partners implicated in both endocytosis and signal transduction, triggers apoptosis even more potently than the wild-type. This observation provides additional support for the importance of the NH(2)-terminal GTPase domain for the apoptotic phenotype. All described effects are dyn2-specific because >200-fold overexpression of dyn1, the 70% identical neuronal isoform, has no effect. Our data suggest that dyn2 can act as a signal transducing GTPase affecting transcriptional regulation.
Fish
K N
KN
Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037, USA.
Schmid
S L
SL
Damke
H
H
D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D034284:Dynamin I; D034281:Dynamins; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D005822:Genetic Vectors / Q000494:pharmacology; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D020033:Protein Isoforms / Q000378:metabolism; D011500:Protein Synthesis Inhibitors; D015398:Signal Transduction / Q000502:physiology*; D013752:Tetracycline / Q000494:pharmacology; D014162:Transfection; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
D020033:Protein Isoforms; D011500:Protein Synthesis Inhibitors; D016159:Tumor Suppressor Protein p53; D014452:Ubiquitins; D006160:Guanosine Triphosphate; D034284:Dynamin I; D020558:GTP Phosphohydrolases; D034281:Dynamins; D013752:Tetracycline