Gamma-secretase subunit PEN-2 (PEN-2)

Gamma-secretase subunit PEN-2 is an essential regulatory component of the gamma-secretase complex, a multi-subunit intramembrane protease responsible for cleaving type I transmembrane proteins such as the Notch receptor and amyloid precursor protein. The gene encoding this protein is PSENEN. As part of the gamma-secretase complex—alongside presenilin, nicastrin, and APH1—PEN‑2 is required for proper assembly and function of the enzyme. This activity is critical in pathways like Notch signaling that govern cell fate decisions during development. In addition to its role in neurodevelopmental processes, aberrant function or mutations in PEN‑2/PSENEN are associated with diseases including Alzheimer’s disease (via altered amyloid beta production) and certain skin disorders such as Dowling-Degos disease and familial acne inversa[1][5][8]. Recent research also indicates that metformin binds to PEN‑2 at therapeutic concentrations; this interaction may contribute to metformin's activation of AMPK through inhibition of v‑ATPase activity[1].

Other names

Presenilin enhancer protein 2PSENENPEN2presenilin enhancer gamma-secretase subunitMDS033

Modulation of gamma-secretase activity and proteolytic processing of substrates such as APP and Notch[1][5]