PT  - JOURNAL ARTICLE
AU  - Thomas Biederer
AU  - Xinwei Cao
AU  - Thomas C. Südhof
AU  - Xinran Liu
TI  - Regulation of APP-Dependent Transcription Complexes by Mint/X11s: Differential Functions of Mint Isoforms
AID  - 10.1523/JNEUROSCI.22-17-07340.2002
DP  - 2002 Sep 01
TA  - The Journal of Neuroscience
PG  - 7340--7351
VI  - 22
IP  - 17
4099  - http://www.jneurosci.org/content/22/17/7340.short
4100  - http://www.jneurosci.org/content/22/17/7340.full
SO  - J. Neurosci.2002 Sep 01; 22
AB  - Mints/X11s are neuron-specific (Mints 1 and 2) and ubiquitous (Mint 3) adaptor proteins composed of isoform-specific N-terminal sequences and common C-terminal phosphotyrosine-binding (PTB) and PDZ domains. We now show that all three Mints bind to the cytoplasmic tail of amyloid-β precursor protein (APP) and presenilins and strongly increase the levels of cellular APP in transfected cells. Immunocytochemistry revealed that in neurons, Mints 1 and 2 were colocalized with APP in the trans-Golgi network, with lower levels throughout the cell body and neurites. Using an APP-dependent transactivation assay that uses a fusion protein of APP coupled to the potent transcription factor Gal4/VP16, we examined the effects of Mints on the proteolytic processing and putative transcriptional function of APP. Although all Mints were biochemically similar, only Mints 1 and 2 but not Mint 3 strongly inhibited transactivation by APP–Gal4/VP16. Inhibition was enhanced by a mutation of the first PDZ domain and by deletion of the PDZ domains or the N-terminal sequences but abolished by inactivation of the PTB- and PDZ domains. Mint 1 also inhibited transactivation by the “precleaved” cytoplasmic tail of APP fused to Gal4/VP16, whereas Fe65 (which binds to APP as strongly as Mints) enhanced transactivation. Our data suggest that Mints 1 and 2 but not Mint 3 have a specific effect on APP function that cannot be explained simply by their interaction with presenilins and occurs at least partly after cleavage of APP. In view of their biochemical similarity, the functional differences among Mints are unexpected, suggesting that Mints 1 and 2 have a brain-specific function related to APP that is not executed by the ubiquitous Mint 3.