DUSPsMKPs

DUSPs, or dual-specificity protein phosphatases, are a family of phosphatases that remove phosphate groups from both phosphotyrosine and phosphoserine/phosphothreonine residues. A subset of these enzymes, known as MKPs (MAP kinase phosphatases), specifically target mitogen-activated protein kinases (MAPKs) such as ERK, JNK, and p38, and thereby regulate MAPK signaling in cells.

Structurally, many MKPs share a conserved catalytic domain that features the active-site motif HCX5R, reflecting a cysteine-based mechanism of dephosphorylation. They also possess MAPK docking motifs that enable selective binding to MAPKs and position the catalytic site for efficient catalysis. The non-catalytic regions of MKPs vary among family members, influencing subcellular localization (nuclear or cytoplasmic) and regulatory interactions.

Substrate specificity among MKPs differs by member. Some preferentially dephosphorylate ERK family MAPKs, others target JNK or p38, and several can act on more than one MAPK. Dephosphorylation of the activation loop on MAPKs occurs at both threonine and tyrosine residues, effectively terminating MAPK signaling and reducing kinase activity. This precision allows MKPs to fine-tune cellular responses to stimuli.

Regulation of DUSPs/MKPs is typically rapid and inducible by stress, cytokines, and growth factors, forming negative feedback loops that dampen MAPK pathway output after activation. Their activity influences processes such as cell proliferation, differentiation, apoptosis, and immune responses. Dysregulation has been linked to diseases including cancer, inflammatory conditions, and neurodegenerative disorders, making DUSPs/MKPs a focus of basic research and therapeutic exploration.