p38 MAPK (MAPK14) phosphorylates full-length CDC25A in vitro on serine residues S76 and S124, but phosphorylates CDC25A peptide fragment only on serine residue S124 (Goloudina et al. 2003). The kinase inhibitor PD-169316, which inhibits p38 MAPKs alpha (MAPK14) and beta (MAPK11), has no effect on CDC25A levels after ultraviolet (UV) irradiation, but inhibits CDC25A degradation and G1/S checkpoint activation in response to osmotic stress, when cells are put in a hypertonic medium (Goloudina et al. 2003). While both S76 and S124 residues of CDC25A are phosphorylated in response to osmotic stress in a p38 MAPK-dependent manner, CDC25A S76A but not CDC25A S124A mutant is stable under osmotic stress (Goloudina et al. 2003). However, ectopic expression of neither CDC25A S76A nor CDC25A S124A nor the double mutant CDC25A S76A;S124A prevents the G1/S checkpoint activation under osmotic stress, implying additional regulatory mechanisms (Goloudina et al. 2003).

Based on studies in Xenopus, besides p38 MAPK, ERK kinases (MAPK1 and MAPK3) and their effector kinase RPS6KA1 (p90RSK) may also contribute to phosphorylation and SCF-BTrCP-mediated degradation of CDC25A (Isoda et al. 2009).