Evidence that dynamin-2 functions as a signal-transducing GTPase

The role of dynamin GTPases in the regulation of receptor-mediated endocyto sis is well established. Here, we present new evidence that the ubiquitousl y expressed isoform dynamin-2 (dyn2) can also function in a signal transduc tion pathway(s). A less than or equal to 5-fold increase of dyn2 relative t o endogenous levels activates the transcription factor p53 and induces apop tosis, as demonstrated by reduced cell proliferation, DNA fragmentation, an d caspase-3 activation. Dyn2-triggered apoptosis occurs only in dividing ce lls and is p53 dependent. A mutant defective in GTP binding does not trigge r apoptosis, indicating that increased levels of dyn2 GTP, rather than prot ein levels per se, are required to transduce signals that activate p53. A t runcated dyn2 lacking the COOH-terminal proline/arginine-rich domain (PRD), which interacts with many SH3 domain-containing partners implicated in bot h endocytosis and signal transduction, triggers apoptosis even more potentl y than the wild-type. This observation provides additional support for the importance of the NH2-terminal GTPase domain for the apoptotic phenotype. A ll described effects are dyn2-specific because >200-fold overexpression of dyn1, the 70% identical neuronal isoform, has no effect. Our data suggest t hat dyn2 can act as a signal transducing GTPase affecting transcriptional r egulation.