PP2C

Protein phosphatase 2C (PP2C) refers to a family of Mg2+/Mn2+-dependent serine/threonine phosphatases that dephosphorylate phosphoserine and phosphothreonine residues. Members are widely distributed across bacteria, archaea, fungi, plants, and animals and are typically monomeric, with a conserved catalytic core that requires divalent metal ions for activity. Their substrate specificity and regulation are influenced by interacting proteins and cellular context.

In plants, PP2Cs are key negative regulators of abscisic acid (ABA) signaling. Well-studied members such as ABI1, ABI2, and HAB1 inhibit SnRK2 kinases in the absence of ABA, maintaining low ABA responses. When ABA is present, receptor families PYR/PYL/RCAR bind ABA and inhibit PP2Cs, allowing SnRK2 activation and downstream stress responses, including stomatal closure and gene expression changes.

In animals and fungi, PP2Cs include well-characterized members such as PPM1A (PP2Cα), PPM1B (PP2Cβ), and PPM1D (Wip1). They participate in cellular stress responses by dephosphorylating targets in pathways controlled by p38 MAPK, JNK, p53, ATM, and Chk proteins, thereby influencing DNA damage signaling, cell cycle progression, and apoptosis. The enzymes are regulated by expression levels, interacting partners, and cellular metal availability.

Biochemically, PP2Cs share a distinctive catalytic core and employ a two-metal-ion mechanism in which metal ions coordinate active-site residues to facilitate dephosphorylation. This catalytic framework distinguishes PP2Cs from other serine/threonine phosphatases such as PP2A and PP2B.

Genetically, eukaryotic PP2Cs are encoded by multiple PPM genes (for example, PPM1A/B/D/E/F in humans), and plant genomes contain numerous PP2C family members with diverse regulatory roles. PP2Cs are targets of research in agriculture for stress tolerance and in biomedicine for cancer and metabolic signaling modulation.