Serine/threonine-protein phosphatase 5

Serine/threonine-protein phosphatase 5 (PPP5C, also called PP5) is a versatile serine/threonine phosphatase that dephosphorylates numerous substrates across multiple signaling pathways, including kinases (ASK1, PRKDC, RAF1), nuclear receptors (NR3C1, PPARG, ESR1, ESR2), SMAD proteins, and tau (TAU/MAPT) (UniProt: P53041). The enzyme regulates diverse cellular processes—apoptosis, DNA damage response, adipogenesis, circadian rhythms, and stress responses—through substrate dephosphorylation in response to hormones, calcium, oxidative stress, and genotoxic damage (UniProt: P53041).

PPP5C is broadly expressed and participates in critical cellular functions including ATM/ATR signaling control, checkpoint activation, and DNA repair mechanisms. It inhibits ASK1-mediated apoptosis under oxidative stress and modulates TGF-beta signaling through SMAD regulation (UniProt: P53041). The enzyme also dephosphorylates and regulates tau phosphorylation.

In Alzheimer's disease, PPP5C is significantly downregulated in post-mortem AD brain tissue compared to age-matched controls (mean log2FC = −0.28; Chaparral AD proteomics). Given PPP5C's established role in tau dephosphorylation and regulation, reduced expression may compromise tau phosphorylation control, potentially contributing to tau pathology accumulation in AD.