| Enzyme Function |
FUNCTION: Catalytic 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). Requires the presence of the other members of the gamma-secretase complex for protease activity (By similarity). 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 (PubMed:10421573, PubMed:11517342). Stimulates cell-cell adhesion via its interaction with CDH1; this stabilizes the complexes between CDH1 (E-cadherin) and its interaction partners CTNNB1 (beta-catenin), CTNND1 and JUP (gamma-catenin) (PubMed:11226248). Under conditions of apoptosis or calcium influx, cleaves CDH1 (PubMed:11953314). This promotes the disassembly of the complexes between CDH1 and CTNND1, JUP and CTNNB1, increases the pool of cytoplasmic CTNNB1, and thereby negatively regulates Wnt signaling (PubMed:11226248). Required for normal embryonic brain and skeleton development, and for normal angiogenesis (PubMed:9160754, PubMed:10421573, PubMed:12834865). Mediates the proteolytic cleavage of EphB2/CTF1 into EphB2/CTF2 (PubMed:17428795). The holoprotein functions as a calcium-leak channel that allows the passive movement of calcium from endoplasmic reticulum to cytosol and is involved in calcium homeostasis (PubMed:16959576). Involved in the regulation of neurite outgrowth (By similarity). Is a regulator of presynaptic facilitation, spike transmission and synaptic vesicles replenishment in a process that depends on gamma-secretase activity. It acts through the control of SYT7 presynaptic expression (PubMed:30429473). {ECO:0000250|UniProtKB:P49768, ECO:0000269|PubMed:10421573, ECO:0000269|PubMed:11226248, ECO:0000269|PubMed:11517342, ECO:0000269|PubMed:11953314, ECO:0000269|PubMed:12834865, ECO:0000269|PubMed:16959576, ECO:0000269|PubMed:17428795, ECO:0000269|PubMed:30429473, ECO:0000269|PubMed:9160754}. |
| Subcellular Location |
SUBCELLULAR LOCATION: Endoplasmic reticulum {ECO:0000250|UniProtKB:P49768}. Endoplasmic reticulum membrane {ECO:0000250|UniProtKB:P49768}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P49768}. Golgi apparatus membrane {ECO:0000250|UniProtKB:P49768}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P49768}. Cytoplasmic granule {ECO:0000250|UniProtKB:P49768}. Cell membrane {ECO:0000269|PubMed:10421573, ECO:0000269|PubMed:11517342}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P49768}. Cytoplasmic vesicle {ECO:0000269|PubMed:10421573, ECO:0000305|PubMed:11517342}. Cell projection, growth cone {ECO:0000250|UniProtKB:P49768}. Cell projection, neuron projection {ECO:0000250|UniProtKB:P49768}. Early endosome {ECO:0000250|UniProtKB:P49768}. Early endosome membrane {ECO:0000250|UniProtKB:P49768}; Multi-pass membrane protein {ECO:0000250|UniProtKB:P49768}. Cell projection, axon {ECO:0000250|UniProtKB:Q4JIM4}. Cell junction, synapse {ECO:0000250|UniProtKB:Q4JIM4}. Note=Translocates with bound NOTCH1 from the endoplasmic reticulum and/or Golgi to the cell surface. Colocalizes with CDH1/2 at sites of cell-cell contact. Colocalizes with CTNNB1 in the endoplasmic reticulum and the proximity of the plasma membrane. Also present in azurophil granules of neutrophils. Colocalizes with UBQLN1 in the cell membrane and in cytoplasmic juxtanuclear structures called aggresomes. {ECO:0000250|UniProtKB:P49768}. |
| Post Translational Modification |
PTM: Heterogeneous proteolytic processing generates N-terminal (NTF) and C-terminal (CTF) fragments of approximately 35 and 20 kDa, respectively. During apoptosis, the C-terminal fragment (CTF) is further cleaved by caspase-3 to produce the fragment, PS1-CTF12. {ECO:0000250|UniProtKB:P49768}.; PTM: After endoproteolysis, the C-terminal fragment (CTF) is phosphorylated on serine residues by PKA and/or PKC. Phosphorylation on Ser-346 inhibits endoproteolysis. {ECO:0000250|UniProtKB:P49768}. |