TY - JOUR
T1 - Microglial signaling by amyloid β protein through mitogen-activated protein kinase mediating phosphorylation of MARCKS
AU - Hasegawa, Hiroshi
AU - Nakai, Masamichi
AU - Tanimukai, Satoshi
AU - Taniguchi, Taizo
AU - Terashima, Akira
AU - Kawamata, Toshio
AU - Fukunaga, Kohji
AU - Miyamoto, Eishichi
AU - Misaki, Kazuyo
AU - Mukai, Hideyuki
AU - Tanaka, Chikako
PY - 2001/8/8
Y1 - 2001/8/8
N2 - 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 β protein (Aβ), a major component of senile plaques, activated MARCKS through a tyrosine kinase and PKC-δ. We have now identified another Aβ 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 Aβ. Extracellulary regulated kinases, the activities of which were induced by Aβ, 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 Aβ 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.
AB - 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 β protein (Aβ), a major component of senile plaques, activated MARCKS through a tyrosine kinase and PKC-δ. We have now identified another Aβ 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 Aβ. Extracellulary regulated kinases, the activities of which were induced by Aβ, 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 Aβ 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.
KW - Amyloid β protein (Aβ)
KW - Extracellular regulated kinase (ERK)
KW - Microglia
KW - Mitogen-activated protein kinase (MAPK)
KW - Myristoylated alanine-rich C kinase substrate (MARCKS)
UR - http://www.scopus.com/inward/record.url?scp=0035828152&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0035828152&partnerID=8YFLogxK
U2 - 10.1097/00001756-200108080-00055
DO - 10.1097/00001756-200108080-00055
M3 - Article
C2 - 11496150
AN - SCOPUS:0035828152
VL - 12
SP - 2567
EP - 2571
JO - NeuroReport
JF - NeuroReport
SN - 0959-4965
IS - 11
ER -