Ubiquitin-mediated degradation of the formin mDia2 upon completion of cell division.
Formins assemble non-branched actin filaments and modulate microtubule dynamics during cell migration and cell division. At the end of mitosis formins contribute to the generation of actin filaments that form the contractile ring. Rho small GTP-binding proteins activate mammalian diaphanous-related (mDia) formins by directly binding and disrupting an intramolecular autoinhibitory mechanism. Although the Rho-regulated activation mechanism is well characterized, little is known about how formins are switched off. Here we reveal a novel mechanism of formin regulation during cytokinesis based on the following observations; 1) mDia2 is degraded at the end of mitosis, 2) mDia2 is targeted for disposal by post-translational ubiquitin modification, 3) forced expression of activated mDia2 yields binucleate cells due to failed cytokinesis, and 4) the cytokinesis block is dependent upon mDia2-mediated actin assembly as versions of mDia2 incapable of nucleating actin but that still stabilize microtubules have no effect on cytokinesis. We propose that the tight control of mDia2 expression and ubiquitin-mediated degradation is essential for the completion of cell division. Because of the many roles for formins in cell morphology, we discuss the relevance of mDia protein turnover in other processes where ubiquitin-mediated proteolysis is an essential component.
DeWard
Aaron D
AD
Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA.
Alberts
Arthur S
AS
D048868:Adaptor Proteins, Signal Transducing / Q000032:analysis* / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002455:Cell Division; D048749:Cytokinesis; D000080865:Formins; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D008239:Lysine / Q000378:metabolism; D051379:Mice; D008938:Mitosis; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D061988:Proteasome Inhibitors; D011499:Protein Processing, Post-Translational; D016415:Sequence Alignment; D025801:Ubiquitin / Q000378:metabolism*; D054875:Ubiquitination
D048868:Adaptor Proteins, Signal Transducing; C484571:DIAPH3 protein, human; D000080865:Formins; D061988:Proteasome Inhibitors; D025801:Ubiquitin; D046988:Proteasome Endopeptidase Complex; D008239:Lysine