aph-1 and pen-2 are required for Notch pathway signaling, gamma-secretase cleavage of betaAPP, and presenilin protein accumulation.
Presenilins are components of the gamma-secretase protein complex that mediates intramembranous cleavage of betaAPP and Notch proteins. A C. elegans genetic screen revealed two genes, aph-1 and pen-2, encoding multipass transmembrane proteins, that interact strongly with sel-12/presenilin and aph-2/nicastrin. Human aph-1 and pen-2 partially rescue the C. elegans mutant phenotypes, demonstrating conserved functions. The human genes must be provided together to rescue the mutant phenotypes, and the inclusion of presenilin-1 improves rescue, suggesting that they interact closely with each other and with presenilin. RNAi-mediated inactivation of aph-1, pen-2, or nicastrin in cultured Drosophila cells reduces gamma-secretase cleavage of betaAPP and Notch substrates and reduces the levels of processed presenilin. aph-1 and pen-2, like nicastrin, are required for the activity and accumulation of gamma-secretase.
Francis
Ross
R
Exelixis, Inc., South San Francisco, CA 94083, USA.
McGrath
Garth
G
Zhang
Jianhuan
J
Ruddy
David A
DA
Sym
Mary
M
Apfeld
Javier
J
Nicoll
Monique
M
Maxwell
Mark
M
Hai
Bing
B
Ellis
Michael C
MC
Parks
Annette L
AL
Xu
Wei
W
Li
Jinhe
J
Gurney
Mark
M
Myers
Richard L
RL
Himes
Carol S
CS
Hiebsch
Ronald
R
Ruble
Cara
C
Nye
Jeffrey S
JS
Curtis
Daniel
D
D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D016282:Aspartic Acid Endopeptidases; D017173:Caenorhabditis elegans; D029742:Caenorhabditis elegans Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D002462:Cell Membrane / Q000378:metabolism* / Q000648:ultrastructure; D002478:Cells, Cultured; D003001:Cloning, Molecular; D029721:Drosophila Proteins; D004331:Drosophila melanogaster; D010450:Endopeptidases / Q000378:metabolism*; D004742:Enhancer Elements, Genetic / Q000235:genetics; D005934:Glucagon / Q000378:metabolism; D052216:Glucagon-Like Peptide 1; D015801:Helminth Proteins / Q000378:metabolism; D018398:Homeodomain Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000302:isolation & purification* / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010446:Peptide Fragments / Q000378:metabolism; D053764:Presenilin-1; D011498:Protein Precursors / Q000378:metabolism; D051880:Receptors, Notch; D017386:Sequence Homology, Amino Acid; D012689:Sequence Homology, Nucleic Acid; D015398:Signal Transduction / Q000235:genetics
C405066:APH-1 protein, C elegans; D016564:Amyloid beta-Protein Precursor; D029742:Caenorhabditis elegans Proteins; D029721:Drosophila Proteins; D015801:Helminth Proteins; D018398:Homeodomain Proteins; C082460:Lin-12 protein, C elegans; D008565:Membrane Proteins; C497759:N protein, Drosophila; C462419:PEN-2 protein, C elegans; C508853:PSEN1 protein, human; D010446:Peptide Fragments; D053764:Presenilin-1; D011498:Protein Precursors; D051880:Receptors, Notch; C410543:aph-2 protein, C elegans; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human