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Aph‐1 is required to regulate Presenilin‐mediated γ‐secretase activity and cell survival in Drosophila wing development
Author(s) -
Cooper Emilie,
Deng WuMin,
Chung HuiMin
Publication year - 2009
Publication title -
genesis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.093
H-Index - 110
eISSN - 1526-968X
pISSN - 1526-954X
DOI - 10.1002/dvg.20478
Subject(s) - presenilin , microbiology and biotechnology , imaginal disc , cytosol , transmembrane protein , mutant , biology , programmed cell death , biochemistry , apoptosis , enzyme , medicine , alzheimer's disease , gene , receptor , disease
Abstract Aph‐1 is a multipass transmembrane protein and an essential component of the Presenilin (Psn)‐mediated γ‐secretase complex. During protease assembly, Aph‐1 stabilizes the newly synthesized Psn holoprotein to facilitate generation of the active form of Psn, which is a Psn‐NTF/Psn‐CTF heterodimer produced through a Presenilinase‐initiated endoproteolytic cleavage of the Psn holoprotein. Although it is clear that loss of Aph‐1 activity leads to failure of Psn heterodimer formation, little is understood about whether Aph‐1 plays a role in regulating γ‐secretase activity in addition to assisting Psn maturation. Using various modified Psn forms that do not require endoproteolysis or have a large deletion of the cytosolic loop, we show that in Drosophila Aph‐1 is still required for γ‐secretase activity independent of its role in promoting Psn endoproteolysis. In addition, our results indicate that Aph‐1 is required to promote cell survival in the wing imaginal disc; aph‐1 mutant cells are lost either through cell death or because of a defect in cell proliferation. This function of Aph‐1 is independent of its role in regulating γ‐secretase activity, but possibly involves downregulating the activity of uncleaved Psn holoprotein. genesis 47:169–174, 2009. © 2009 Wiley‐Liss, Inc.