The pseudophosphatase MK‐STYX (mitogen‐activated protein kinase phosphoserine/threonine/tyrosine‐binding protein) has been implicated in the stress response pathway. The expression of MK‐STYX inhibits the assembly of stress granules, which are cytoplasmic storage sites for mRNA that form as a protective mechanism against stressors such as heat shock, UV irradiation and hypoxia. Furthermore, MK‐STYX interacts with a key component of stress granules: G3BP‐1 (Ras‐GTPase activating protein SH3 domain binding protein‐1). Because G3BP‐1 dephosphorylation at Ser149 induces stress granule assembly, we initially hypothesized that the inhibition of stress granules by MK‐STYX was G3BP‐1 phosphorylation‐dependent. However, in the present study, using MK‐STYX constructs and G3BP‐1 phosphomimetic or nonphosphorylatable mutants, we show that MK‐STYX inhibits stress granule formation independently of G3BP‐1 phosphorylation at Ser149. The introduction of point mutations at the ‘active site’ of MK‐STYX that convert serine and phenylalanine to histidine and cysteine, respectively, is sufficient to generate an active enzyme. In separate experiments, we show that this active mutant, MK‐STYXactive, has opposite effects to wild‐type MK‐STYK. Not only does MK‐STYXactive induce stress granules, but also it has the capacity to dephosphorylate G3BP‐1. Taken together, these results provide evidence that the pseudophosphatase MK‐STYX plays a key role in the cellular response to stress.