Phosphatases

Phosphatases are enzymes that catalyze the hydrolysis of phosphate monoesters, removing a phosphate group from substrates such as proteins, lipids, or nucleotides. They counter kinases in phosphorylation signaling and regulate myriad cellular processes. Most phosphatases rely on specific active-site chemistry, often involving metal ions, catalytic cysteine or aspartate residues, and water as the nucleophile.

Major classes include protein tyrosine phosphatases (PTPs), serine/threonine phosphatases (PPs), dual-specificity phosphatases (DUSPs) that act on both serine/threonine and tyrosine residues, and lipid/inositol phosphatases such as PTEN and SHIP. Among PTPs, cysteine-based catalysis is common; many serine/threonine phosphatases are metal-dependent and function in complexes with regulatory subunits (for example PP1, PP2A, and calcineurin). The HAD (haloacid dehalogenase) phosphatase superfamily is another broad group with a distinct catalytic mechanism.

Biological roles of phosphatases are diverse, including regulation of signal transduction pathways, metabolism, cell cycle progression, development, and immune and nervous system function. Activity is tightly controlled by subunit composition and localization, post-translational modifications, oxidative state, and endogenous inhibitors.

Notable examples and clinical relevance include PTEN, a lipid phosphatase that dephosphorylates PI(3,4,5)P3 and acts as a tumor suppressor; SHP2 (PTPN11), which modulates RAS/MAPK signaling; calcineurin (PP2B), which activates NFAT transcription factors; and DUSPs that fine-tune MAPK activity. Inhibitors such as vanadate (broad PTP inhibitor) and okadaic acid (PP1/PP2A inhibitor) are used as research tools.

Dysfunction or misregulation of phosphatases is linked to cancer, metabolic diseases, and autoimmune conditions. Phosphatases are important targets for therapeutic development and key components of cellular signaling networks.