Affiliations: [a] Buck Institute for Age Research, Novato, CA, USA | [b] Department of Natural Sciences and Mathematics, Dominican University of California, San Rafael, CA, USA | [c] Department of Neurology, University of California San Francisco, San Francisco, CA, USA
Correspondence:
[*]
Correspondence to: Dale E. Bredesen, Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA. Tel.: +1 415 209 2090; Fax: +1 415 209 2230; E-mail: dbredesen@buckinstitute.org.
Note: [1] Present address: Graduate Program in Biology, Watson School of Biology, Cold Spring Harbor Laboratory, CSH, NY, USA.
Abstract: The amyloid-β protein precursor (AβPP) has been implicated in Alzheimer's disease (AD) not only as a precursor of the amyloid-β peptide but also as a mediator of signal transduction. We recently identified novel mediators of AβPP signaling via interactions with Mint/X11 family proteins Mint1 and Mint3. These mediators include transcriptional co-activators Taz and Yap. Here we show that Taz and Yap also mediate signaling via the AβPP paralogues APLP1 and APLP2 through interactions with Mint1 and Mint3. APLP1 and APLP2 formed transcriptionally active triple protein complexes with the adaptor protein Mint3 and each of the transcriptional regulators Taz and Yap, and complex formation was regulated by the γ-secretase cleavage of APLP1 and APLP2. The presence of Mint1 instead of Mint3 in the complex prevented its translocation to the nucleus. APLP1 displayed much lower transactivation levels compared to AβPP and APLP2. These results indicate that all three AβPP family members are capable of activating gene transcription via Mint3-Taz and Mint3-Yap.
Keywords: Amyloid precursor-like protein (APLP), γ-secretase, gene transcription, triple protein complex
