Dual specificity phosphatase 26 (DUSP26)

Dual specificity phosphatase 26 (DUSP26) is an atypical member of the protein tyrosine phosphatase family, capable of dephosphorylating both phosphotyrosine and phosphothreonine residues on substrates, notably both MAP kinases and non-MAP kinase proteins such as the tumor suppressor p53[1][3]. DUSP26 contains a non-catalytic N-terminal domain and a catalytic C-terminal domain that features a canonical "HCX5R" active site motif typical for phosphatases; the structure regulates substrate access and enzymatic activity[1][3]. DUSP26 is mostly nuclear, with tissue-restricted expression (notably brain, heart, and skeletal muscle)[1]. It directly modulates key intracellular signaling pathways involved in cell survival, proliferation, and apoptosis—including the MAPK cascade—by dephosphorylating substrates such as ERK, JNK, p38, and p53[1][2][3]. DUSP26 is implicated in a range of diseases, notably with conflicting roles in different cancers: it can function as an oncogene or a tumor suppressor depending on context (e.g., is upregulated in neuroblastoma where it inactivates p53, but downregulated in glioblastoma, acting as a tumor suppressor)[1]. DUSP26 also plays protective roles in cardiac hypertrophy by modulating MAPK pathway activation[2], and contributes to nonalcoholic fatty liver disease regulation by affecting the TAK1–p38/JNK pathway[2]. DUSP26 is a validated research target with small-molecule inhibitors showing proof-of-principle activity in cancer cell studies, but current inhibitors lack specificity for clinical use[1].

Other names

Dual specificity protein phosphatase 26DUSP24LDP4MKP8NATA1SKRP3DSP-4LDP-4MAP kinase phosphatase 8MKP-8MGC1136NEAPDual specificity phosphatase SKRP3Low-molecular-mass dual-specificity phosphatase 4Mitogen-activated protein kinase phosphatase 8Novel amplified gene in thyroid anaplastic cancerneuroendocrine-associated phosphatase

Inhibition of DUSP26 enzymatic activity (phosphatase inhibition), leading to increased phosphorylation of target proteins such as p53 or MAPKs[1]