Identification of a carboxyl-terminal diaphanous-related formin homology protein autoregulatory domain.
Mammalian and fungal Diaphanous-related formin homology (DRF) proteins contain several regions of conserved sequence homology. These include an amino-terminal GTPase binding domain (GBD) that interacts with activated Rho family members and formin homology domains that mediate targeting or interactions with signaling kinases and actin-binding proteins. DRFs also contain a conserved Dia-autoregulatory domain (DAD) in their carboxyl termini that binds the GBD. The GBD is a bifunctional autoinhibitory domain that is regulated by activated Rho. Expression of the isolated DAD in cells causes actin fiber formation and stimulates serum response factor-regulated gene expression. Inhibitor experiments show that the effects of exogenous DAD expression are dependent upon cellular Dia proteins. Alanine substitution of DAD consensus residues that disrupt GBD binding also eliminate DAD biological activity. Thus, DAD expression activates nuclear signaling and actin remodeling by mimicking activated Rho and unlatching the autoinhibited state of the cellular complement of Dia proteins.
Alberts
A S
AS
Laboratory of Cell Structure and Signal Integration, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA. art.alberts@vai.org
D016475:3T3 Cells; D000199:Actins / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D002352:Carrier Proteins / Q000378:metabolism*; D003599:Cytoskeleton / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D005326:Fetal Proteins / Q000378:metabolism*; D000080865:Formins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D017386:Sequence Homology, Amino Acid; D026362:Serum Response Factor; D015398:Signal Transduction
D000199:Actins; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C491464:Diap1 protein, mouse; D005326:Fetal Proteins; D000080865:Formins; D009687:Nuclear Proteins; D026362:Serum Response Factor