The founding formin homology protein family members were implicated early on as being involved in regulating cytoskeletal remodeling pathways, as formin protein mutations in Drosophila and yeast lead to obvious actin cytoskeleton defects. The discovery that these proteins associated directly with small Rho family GTPases confirmed these results and greatly enhanced our understanding of their function. The mammalian diaphanous-related formins (DRFs) were subsequently recognized as being involved in activation of serum response factor (SRF), tying formins to transcriptional regulation. In the past few years, much progress has been made in demonstrating how DRFs act as both downstream effectors and upstream modulators of Rho GTPase signaling. These functions are important for regulation of both actin and microtubule cytoskeletal structures, and affect cellular processes such as the establishment of polarity, vesicle movement, and focal adhesion remodeling. The connection of DRFs to the SH3 domain-containing protein, Src, has also been described as being important to several basic cellular functions. While still unresolved, extensive work has been carried out on how DRFs mediate SRF activation, and the importance of this to the regulation of cytoskeletal structure. This review will focus on the role of formins in cytoplasmic signal transduction pathways and the downstream effects on the regulation of gene expression.
Plakins are a family of giant cytoskeleton binding proteins. One member of this group is bullous pemphigoid antigen 1 (Bpag1)/dystonin, which has neuronal and muscle isoforms that consist of actin-binding and microtubule-binding domains at either end separated by a plakin domain and several spectrin repeats. The better-characterized epithelial isoform has only the plakin domain in common with the neuronal and muscle isoforms. Here, we have analyzed the localization of muscle/neuronal (Bpag1a/b) isoforms and the epithelial (Bpag1e) isoform within C2C12 myoblast cells. Although an antibody specific to Bpag1a/b isoform 2 detected protein co-aligning actin stress fibers, this same antibody and two Bpag1e antibodies predominantly detected protein in the nuclei. A Bpag1a/b isoform 2 N-terminal fusion protein containing the plakin domain also localized to actin stress fibers and to nuclei.Within the plakin domain, we characterized a functional nuclear localization signal, which was responsible for localization of the fusion protein to the nucleus. Bpag1a/b isoform 1 N-terminal fusion proteins differed in their interaction with the actin cytoskeleton and with their ability to localize to the nucleus, suggesting that Bpag1 isoforms with different N-termini have differing roles. These results show the importance of N-terminal domains in dictating the localization and function of Bpag1 isoforms. We provide the first indication that Bpag1 is not strictly a cytoplasmic/membrane protein but that it can also localize to the nucleus.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.