Interaction of ASK1 and the beta-amyloid precursor protein in a stress-signaling complex.
The amyloid precursor protein (APP) is a type I transmembrane protein translocated to neuronal terminals, whose function is still unknown. The C-terminus of APP mediates its interaction with cellular adaptor and signaling proteins, some of which signal to the stress-activated protein kinase (SAPK) pathway. Here we show that ASK1, a MAPKKK that activates two SAPKs, c-Jun N-terminal-kinase (JNK) and p38, is present in a complex containing APP, phospho-MKK6, JIP1 and JNK1. In primary neurons deprived of growth factors, as well as in brains of (FAD)APP-transgenic mice, ASK1 was upregulated in neuronal projections, where it interacted with APP. In non-transgenic brains, ASK1 and APP associated mainly in the ER. Our results indicate that recruitment of ASK1 to stress-signaling complexes assembled with APP may be triggered and enhanced by cellular stress. Thus, ASK1 may be the apical MAPKKK in a signaling complex assembled with APP as a response to stress.
Galvan
Veronica
V
Buck Institute for Age Research, 8001 Redwood Blvd., Novato, CA 94945, USA.
Banwait
Surita
S
Spilman
Patricia
P
Gorostiza
Olivia F
OF
Peel
Alyson
A
Ataie
Marina
M
Crippen
Danielle
D
Huang
Wei
W
Sidhu
Gurleen
G
Ichijo
Hidenori
H
Bredesen
Dale E
DE
D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D048669:MAP Kinase Kinase 6 / Q000378:metabolism; D048848:MAP Kinase Kinase Kinase 5 / Q000737:chemistry / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism; D009474:Neurons / Q000737:chemistry / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology*; D021381:Protein Transport / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D013572:Synaptic Vesicles / Q000378:metabolism
D016564:Amyloid beta-Protein Precursor; D048055:Mitogen-Activated Protein Kinase 8; D048848:MAP Kinase Kinase Kinase 5; C482858:MAP3K5 protein, human; D048669:MAP Kinase Kinase 6
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