Novel mediators of amyloid precursor protein signaling.
Multiple recent reports implicate amyloid precursor protein (APP) signaling in the pathogenesis of Alzheimer's disease, but the APP-dependent signaling network involved has not been defined. Here, we report a novel consensus sequence for interaction with the PDZ-1 and PDZ-2 domains of the APP-interacting proteins Mint1, Mint2, and Mint3 (X11alpha, X11beta, and X11gamma), and multiple novel interactors for these proteins, with the finding that transcriptional coactivators are highly represented among these interactors. Furthermore, we show that Mint3 interaction with a set of the transcriptional coactivators leads to nuclear localization and transactivation, whereas interaction of the same set with Mint1 or Mint2 prevents nuclear localization and transactivation. These results define new mediators of the signal transduction network mediated by APP.
Swistowski
Andrzej
A
Buck Institute for Age Research, Novato, California 94945, USA.
Zhang
Qiang
Q
Orcholski
Mark E
ME
Crippen
Danielle
D
Vitelli
Cathy
C
Kurakin
Alexei
A
Bredesen
Dale E
DE
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry / Q000502:physiology*; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism* / Q000502:physiology; D015820:Cadherins / Q000737:chemistry / Q000502:physiology*; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D002460:Cell Line; D057166:High-Throughput Screening Assays; D006801:Humans; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000502:physiology*; D054731:PDZ Domains / Q000502:physiology; D011485:Protein Binding / Q000502:physiology; D025941:Protein Interaction Mapping; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000502:physiology*; D015533:Transcriptional Activation / Q000502:physiology
C079091:APBA1 protein, human; C491636:APBA2 protein, human; C117536:APBA3 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D015820:Cadherins; D002352:Carrier Proteins; D009419:Nerve Tissue Proteins