Formins are a conserved family of proteins that govern cytoskeletal remodeling in the cell. Common among all formins is the Formin Homology-2 domain, which is responsible for nucleating and elongating non-branched actin filaments. One particular subset of the formin family, the mammalian Diaphanous-related (mDia) formins, are downstream effectors for small GTP-binding proteins whose activities are controlled by an intricate autoregulatory mechanism.

Actin remodeling plays a central role during vesicle trafficking. It was found that the small GTPase RhoB interacts with mDia2 on intracellular vesicles. In addition, interfering with RhoB or mDia2 activity diminished vesicle movement. These studies suggest that controlled actin dynamics are required for normal trafficking events, and mDia formins play a significant role in this process.

A mouse model of human myelodysplastic syndrome was previously generated by knocking out Drf1, the gene that encodes mDia1. These studies led to the generation of mice lacking both mDia1 and RhoB expression, because of the known interaction between these two proteins and because of the proposed tumor suppressor function of RhoB. It was found that the additional loss of RhoB expression enhances the myelodysplastic phenotype of mDia1 knockout mice. The mechanism by which mDia1 and RhoB loss contributes to the observed phenotype may be centered on the actin sensing pathway mediated by serum response factor, an important transcription factor that is activated in response to mDia activity.

Formins are required during cell division to mediate the assembly of the contractile actin ring for the completion of cytokinesis. However, important questions remained about the specific role of mDia2 during cell division. It was discovered that mDia2 expression is cell cycle-dependent and is degraded by ubiquitin-mediated proteolysis. mDia2 proteolytic degradation is a regulatory mechanism to shut down formin activity during cell division and is likely to function in other contexts as well. Preliminary studies suggest that the anaphase-promoting complex serves as the ubiquitin ligase to promote mDia2 ubiquitination.

Despite the numerous cytoskeletal remodeling events controlled by formins, relatively few instances have directly implicated formins in disease processes. A more extensive characterization of formin function will be important to determine their contributions to normal cell biology and to disease.