DUSPs

Dual-specificity phosphatases (DUSPs) are a family of protein tyrosine phosphatases characterized by their ability to remove phosphate groups from both phosphotyrosine and phosphoserine/phosphothreonine residues. They act as negative regulators of mitogen-activated protein kinase (MAPK) signaling by dephosphorylating MAPKs such as ERK1/2, JNK, and p38. The DUSP family is commonly referred to as the MKP family, reflecting their role as MAP kinase phosphatases.

Most DUSPs share a conserved catalytic domain containing the HCX5R motif, a hallmark of cysteine-based phosphatases that coordinates catalysis. They are usually around 20–40 kDa and often possess N- and/or C-terminal regulatory regions that influence subcellular localization and substrate recognition. Many DUSPs include docking motifs, such as kinase interaction motifs (KIMs), that facilitate binding to MAPKs, leading to efficient dephosphorylation. The catalytic activity and localization of DUSPs can be modulated by cellular signals, making them dynamic regulators of signaling networks.

Substrate specificity among DUSPs varies: while the family is defined by dual specificity, individual members may preferentially target specific MAPKs or operate in particular cellular compartments. They can be inducible by growth factors or stress and frequently provide negative feedback to MAPK signaling, contributing to the termination and fine-tuning of responses.

Physiological roles of DUSPs include regulation of cell proliferation, differentiation, and stress responses. Dysregulation of DUSP activity has been linked to cancer, inflammatory diseases, and fibrosis, making these enzymes relevant as potential therapeutic targets to modulate MAPK-driven pathologies.