Formins are evolutionarily conserved actin nucleators involved in the formation of filopodia, lamellipodia and stress fibres. Over a decade ago, the compound SMIFH2 was identified as an inhibitor of the FH2 domain of formins and has since been used in numerous studies of formin-dependent actin polymerisation in different species. However, from its chemical composition, specificity of SMIFH2 for the formin FH2 domain is not apparent. In a joint effort, the groups of Alexander Bershadsky, Virgile Viasnoff and James Sellers (Nishimura et al., 2021) now analyse in more detail its effects, prompted by the surprising observation that treatment of fibroblasts with SMIFH2 inhibits the contraction of stabilised stress fibres and movement of actin arcs. As these effects phenocopy the addition of the known myosin II inhibitor blebbistatin, this raises the possibility that SMIFH2 affects myosin 2. Indeed, the authors show that SMIFH2 inhibits the ATPase activity of myosin and the ability of actin filaments to translocate in an in vitro gliding assay. Although SMIFH2 affects myosin 2A only at a relatively high concentration, other myosins, including myosin 10, myosin 7 and myosin 5, are inhibited by SMIFH2 in smaller doses, and some with greater potency than formins. Therefore, these findings not only caution against misinterpretation when using this inhibitor to study the actomyosin cytoskeleton and cell motility, but also highlight the need for novel compounds that are truly specific for formins.
Off-target effects of the formin inhibitor SMIFH2
Off-target effects of the formin inhibitor SMIFH2. J Cell Sci 15 April 2021; 134 (8): e134–e0803. doi:
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