Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogen-activated protein kinase and c-Jun terminal kinase.

TY - JOUR

T1 - Dishevelled regulates the metabolism of amyloid precursor protein via protein kinase C/mitogen-activated protein kinase and c-Jun terminal kinase.

AU - Mudher, A

AU - Chapman, S

AU - Richardson, J

AU - Asuni, A

AU - Gibb, G

AU - Pollard, C

AU - Killick, R

AU - Iqbal, T

AU - Raymond, L

AU - Varndell, I

AU - Sheppard, P

AU - Makoff, A

AU - Gower, E

AU - Soden, P E

AU - Lewis, P

AU - Murphy, M

AU - Golde, T E

AU - Rupniak, H T

AU - Anderton, B H

AU - Lovestone, S

PY - 2001/7/15

Y1 - 2001/7/15

N2 - 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 (sAPP alpha), and glycogen synthase kinase (GSK)-3 beta is known to increase tau phosphorylation. Both PKC and GSK-3 beta are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPP alpha 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-3 beta. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.

AB - 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 (sAPP alpha), and glycogen synthase kinase (GSK)-3 beta is known to increase tau phosphorylation. Both PKC and GSK-3 beta are components of the wnt signaling cascade. Here we demonstrate that overexpression of another member of this pathway, dishevelled (dvl-1), increases sAPP alpha 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-3 beta. Therefore, both APP metabolism and tau phosphorylation are potentially linked through wnt signaling.

M3 - Article

SN - 1529-2401

VL - 21

SP - 4987

EP - 4995

JO - Journal of Neuroscience

JF - Journal of Neuroscience

IS - 14

ER -