Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogen-activated protein kinase and c-Jun terminal kinase.
Alzheimer's disease (AD) is a disorder of two pathologies: amyloid plaques, the core of which is a peptide derived from the amyloid precursor protein (APP), and neurofibrillary tangles composed of highly phosphorylated tau. Protein kinase C (PKC) is known to increase non-amyloidogenic alpha-secretase cleavage of APP, producing secreted APP (sAPPalpha), and glycogen synthase kinase (GSK)-3beta is known to increase tau phosphorylation. Both PKC and GSK-3beta are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPPalpha production. The dishevelled action on APP is mediated via both c-jun terminal kinase (JNK) and protein kinase C (PKC)/mitogen-activated protein (MAP) kinase but not via p38 MAP kinase. These data position dvl-1 upstream of both PKC and JNK, thereby explaining the previously observed dual signaling action of dvl-1. Furthermore, we show that human dvl-1 and wnt-1 also reduce the phosphorylation of tau by GSK-3beta. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.
Mudher
A
A
Departments of Neuroscience and Psychiatry, Institute of Psychiatry, King's College London, London SE5 8AF, United Kingdom.
Chapman
S
S
Richardson
J
J
Asuni
A
A
Gibb
G
G
Pollard
C
C
Killick
R
R
Iqbal
T
T
Raymond
L
L
Varndell
I
I
Sheppard
P
P
Makoff
A
A
Gower
E
E
Soden
P E
PE
Lewis
P
P
Murphy
M
M
Golde
T E
TE
Rupniak
H T
HT
Anderton
B H
BH
Lovestone
S
S
D048868:Adaptor Proteins, Signal Transducing; D000544:Alzheimer Disease / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases; D016564:Amyloid beta-Protein Precursor / Q000235:genetics / Q000378:metabolism*; D016282:Aspartic Acid Endopeptidases; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D000072261:Dishevelled Proteins; D010450:Endopeptidases / Q000378:metabolism; D015870:Gene Expression; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism*; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000378:metabolism / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; C000606578:DVL1 protein, human; D000072261:Dishevelled Proteins; D010750:Phosphoproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D016875:tau Proteins; D038341:Glycogen Synthase Kinases; D011493:Protein Kinase C; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3; D053829:Amyloid Precursor Protein Secretases; D010450:Endopeptidases; D016282:Aspartic Acid Endopeptidases; C509280:BACE1 protein, human