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© The Rockefeller University Press, 0021-9525/2000//145 $5.00
The Journal of Cell Biology, Volume 150, Number 1, , 2000 145-154

Evidence That Dynamin-2 Functions as a Signal-Transducing Gtpase

^a Department of Cell Biology, The Scripps Research Institute, La Jolla, California 92037
Department of Cell Biology, The Scripps Research Institute, IMM-11, 10550 N. Torrey Pines Rd., La Jolla, CA 92037.(858) 784-9126(858) 784-2311

damke{at}scripps.edu

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 NH₂-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.

Key Words: dynamin • apoptosis • p53 • GTPase • endocytosis

© 2000 The Rockefeller University Press

Abbreviations used in this paper: Ad, adenovirus; dyn, dynamin; moi, multiplicity of infection; pfu, plaque forming unit; PRD, proline/arginine-rich domain; tTA, tetracycline-responsive transcription activator.

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