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.
- Amyloid β protein (Aβ)
- Extracellular regulated kinase (ERK)
- Mitogen-activated protein kinase (MAPK)
- Myristoylated alanine-rich C kinase substrate (MARCKS)
ASJC Scopus subject areas