Recombinant Human Gamma-secretase subunit PEN-2 (PSENEN) Protein

Function

Essential subunit of the gamma-secretase complex, an endoprotease complex that catalyzes the intramembrane cleavage of integral membrane proteins such as Notch receptors and APP (amyloid-beta precursor protein) (PubMed:12522139, PubMed:12679784, PubMed:12740439, PubMed:12763021, PubMed:24941111, PubMed:30598546, PubMed:30630874). The gamma-secretase complex plays a role in Notch and Wnt signaling cascades and regulation of downstream processes via its role in processing key regulatory proteins, and by regulating cytosolic CTNNB1 levels (Probable). PSENEN modulates both endoproteolysis of presenilin and gamma-secretase activity (PubMed:12522139, PubMed:12679784, PubMed:12740439, PubMed:12763021, PubMed:24941111). Besides its role in gamma-secretase complex, acts as a regulator of AMP-activated protein kinase (AMPK) activity in response to calorie restriction: binds metformin, an antidiabetic drug, promoting association with ATP6AP1, a subunit of the V-ATPase complex, leading to V-ATPase complex inhibition on lysosomes and AMPK activation via the AXIN1-STK11/LKB1 axis (By similarity)

Subcellular Location

Endoplasmic reticulum membrane (Multi-pass membrane protein); Golgi apparatus, Golgi stack membrane (Multi-pass membrane protein); Cell membrane (Multi-pass membrane protein); Membrane (Multi-pass membrane protein)

Disease Association

Acne inversa, familial, 2, with or without Dowling-Degos disease (ACNINV2) : An autosomal dominant form of acne inversa, a chronic relapsing inflammatory disease of the hair follicles characterized by recurrent draining sinuses, painful skin abscesses, and disfiguring scars. Manifestations typically appear after puberty. Some ACNINV2 patients also exhibit reticulate hyperpigmentation consistent with Dowling-Degos disease. [The disease is caused by variants affecting the gene represented in this entry]

Tissue Specificity

Widely expressed. Expressed in leukocytes, lung, placenta, small intestine, liver, kidney, spleen thymus, skeletal muscle, heart and brain

Subunit

The functional gamma-secretase complex is composed of at least four polypeptides: a presenilin homodimer (PSEN1 or PSEN2), nicastrin (NCSTN), APH1 (APH1A or APH1B) and PSENEN

• Zhao M. et al. Novel genes expressed in hematopoietic stem/progenitor cells from myelodysplastic syndrome patients. (DEC-)
• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Steiner H. et al. PEN-2 is an integral component of the gamma-secretase complex required for coordinated expression of presenilin and nicastrin. — J. Biol. Chem. (2002)
• Francis R. et al. aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation. — Dev. Cell (2002)
• Luo W.-J. et al. PEN-2 and APH-1 coordinately regulate proteolytic processing of presenilin 1. — J. Biol. Chem. (2003)
• Crystal A.S. et al. Membrane topology of gamma-secretase component PEN-2. — J. Biol. Chem. (2003)
• Marlow L. et al. APH1, PEN2, and nicastrin increase Abeta levels and gamma-secretase activity. — Biochem. Biophys. Res. Commun. (2003)