GSK-3β Directly Phosphorylates and Activates MARK2/PAR-1

Abstract

In Alzheimer disease (AD), the microtubule-associated protein tau is found hyperphosphorylated in paired helical filaments. Among many phosphorylated sites in tau, Ser-262 is the major site for abnormal phosphorylation of tau in AD brain. The kinase known to phosphorylate this particular site is MARK2, whose activation mechanism is yet to be studied. Our first finding that treatment of cells with LiCl, a selective inhibitor of another major tau kinase, glycogen synthase kinase-3␤ (GSK-3␤), inhibits phosphorylation of Ser-262 of tau led us to investigate the possible involvement of GSK-3␤ in MARK2 activation. In vitro kinase reaction revealed that recombinant GSK-3␤ indeed phosphorylates MARK2, whereas it failed to phosphorylate Ser-262 of tau. Our further findings led us to conclude that GSK-3␤ phosphorylates MARK2 on Ser-212, one of the two reported phosphorylation sites (Thr-208 and Ser-212) found in the activation loop of MARK2. Down-regulation of either GSK-3␤ or MARK2 by small interfering RNAs suppressed the level of phosphorylation on Ser-262. These results, respectively, indicated that GSK-3␤ is responsible for phosphorylating Ser-262 of tau through phosphorylation and activation of MARK2 and that the phosphorylation of tau at this particular site is predominantly mediated by a GSK-3␤-MARK2 pathway. These findings are of interest in the context of the pathogenesis of AD.

Regulation of the polarity kinases PAR-1/MARK by 14-3-3 interaction and phosphorylation

“…Glycogen synthase kinase 3 (GSK3) (Frame and Cohen, 2001), was recently suggested to phosphorylate MARK2, potentially at a T-loop residue (S312) located four residues C-terminal to the threonine phosphorylated by LKB1 (Kosuga et al, 2005). It would be interesting to investigate whether proline-directed kinases and GSK3 could phosphorylate MARK2 at sites other than S312, and whether these phosphorylations can be modulated by inhibitors and/or extracellular stimuli that affect proline-directed kinase/GSK3 activity.…”

A Calcium- and Calmodulin-Dependent Kinase Iα/Microtubule Affinity Regulating Kinase 2 Signaling Cascade Mediates Calcium-Dependent Neurite Outgrowth

“…It seems likely that several pathways converge to activate MARK2. For example, MARK kinase, LKB1 kinase, Pim-1, and GSK-3 can all phosphorylate MARK2 within its kinase domain (Timm et al, 2003;Bachmann et al, 2004;Lizcano et al, 2004;Kosuga et al, 2005), suggesting that multiple kinases, which may be differentially expressed in N2a cells and hippocampal neurons, potentially converge on MARK2 to regulate its activity. Similarly, downstream effectors of CaMKI may differ between neuronal types.…”

Helicobacter pylori CagA promotes Snail-mediated epithelial–mesenchymal transition by reducing GSK-3 activity

“…Consistent with previous findings that the EPIYA repeated region is responsible for the activation of b-catenin 45 , we found that a C-terminal region having an EPIYIA and multimerization domain plays an important role in binding to and depletion of GSK-3. Intriguingly, GSK-3 can phosphorylate PAR1/MARK2, which is responsible for tau phosphorylation in Alzheimer disease 46 .…”