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Abstract: DMKP‐3 is a Drosophila dual‐specificity phosphatase, which has high substrate specificity for Drosophila extracellular signal‐regulated kinases (DERK). By in vitro reconstitution experiments, we found that DERK activates DMKP‐3. Moreover, DMKP‐3 was specifically activated by the addition of DERK but not by DJNK, Dp38, or Sevenmaker DERK D334N, a DMKP‐3‐ binding mutant. The phosphatase activity of DMKP‐3‐R56A/R57A, a DERK‐binding mutant, was not increased by DERK. Significantly, mammalian MKP‐3 was also found to be activated by DERK. This cross‐reactivity suggests a high level of conservation of the activation mechanism of ERK‐specific phosphatases in Drosophila and mammals. When DMKP‐3 was co‐expressed with DERK in Drosophila Schneider cells, DMKP‐3 protein levels increased, but this was not observed for the co‐expressions of DJNK or Dp38. The stabilizations …