Microglial signaling by amyloid beta protein through mitogen-activated protein kinase mediating phosphorylation of MARCKS.
Myristoylated alanine-rich C kinase substrate (MARCKS), an acidic protein associated with cell motility and phagocytosis, is activated upon phosphorylation by protein kinase C (PKC) and proline-directed protein kinases. In Alzheimer disease (AD), activated microglia expressing MARCKS migrates around senile plaques. We reported that amyloid beta protein (A beta), a major component of senile plaques, activated MARCKS through a tyrosine kinase and PKC-delta. We have now identified another A beta signaling pathway through a mitogen-activated protein kinase (MAPK) involved in the phosphorylation of MARCKS and analysed cross-talk between PKC and MAPK pathways in primary cultured rat microglia. A selective inhibitor for MAPK kinase, PD098059, significantly inhibited the phosphorylation of MARCKS induced by A beta. Extracellulary regulated kinases, the activities of which were induced by A beta, directly phosphorylated a recombinant MARCKS in vitro. The MAPK pathway was sensitive to wortmannin, but not to a PKC inhibitor or to tyrosine kinase inhibitors. The activation of PKC by A beta was not sensitive to wortmannin. Our findings suggest involvement of the MAPK pathway through phosphoinositol 3-kinase in the phosphorylation of MARCKS in rat cultured microglia, an event may be associated with mechanisms activating microglia in AD.
Hasegawa
H
H
Hyogo Institute for Aging Brain and Cognitive Disorders, 520 Saisho-ko, Himeji 670-0981, Japan.
Nakai
M
M
Tanimukai
S
S
Taniguchi
T
T
Terashima
A
A
Kawamata
T
T
Fukunaga
K
K
Miyamoto
E
E
Misaki
K
K
Mukai
H
H
Tanaka
C
C
D016229:Amyloid beta-Peptides / Q000378:metabolism* / Q000494:pharmacology; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D000906:Antibodies; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D008565:Membrane Proteins; D017628:Microglia / Q000166:cytology / Q000378:metabolism*; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D000076250:Myristoylated Alanine-Rich C Kinase Substrate; D009281:Naphthalenes / Q000494:pharmacology; D010446:Peptide Fragments / Q000378:metabolism* / Q000494:pharmacology; D010750:Phosphoproteins / Q000276:immunology; D010761:Phosphorus Radioisotopes; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051745:Protein Kinase C-delta; D011506:Proteins / Q000378:metabolism*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D020239:Receptor Cross-Talk / Q000187:drug effects / Q000502:physiology; D000077191:Wortmannin
D016229:Amyloid beta-Peptides; D000730:Androstadienes; D000906:Antibodies; D004791:Enzyme Inhibitors; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; C000619712:Marcks protein, rat; D008565:Membrane Proteins; D009281:Naphthalenes; D010446:Peptide Fragments; D010750:Phosphoproteins; D010761:Phosphorus Radioisotopes; D011506:Proteins; C078592:amyloid beta-protein (1-40); C074636:amyloid beta-protein (25-35); D000076250:Myristoylated Alanine-Rich C Kinase Substrate; C497260:Prkcd protein, rat; D011493:Protein Kinase C; D051745:Protein Kinase C-delta; D020928:Mitogen-Activated Protein Kinases; C058819:calphostin C; D000077191:Wortmannin