Modes of regulating MARK. The diagram summarizes known or plausible modes of MARK regulation that would affect the phosphorylation of tau and hence the stability of microtubules and the aggregation of tau. Activation via phosphorylation by MARKK (red) or LKB1 (grey) at T208 in the activation loop [17,18]. Inhibition by binding of PAK5 (green) to the catalytic domain . Inhibition via phosphorylation by GSK3β (blue) at S212 in the activation loop . Regulation by interaction of the UBA domain with ubiquitin (cyan) (not proven but suggested by X-ray structure) . Regulation by interaction of the CD motif with a cofactor (yellow), in analogy with MAP kinases where upstream or downstream kinases can be bound [24,27]. Localization by interaction of the catalytic domain with the adaptor protein 14-3-3 (violet) (in analogy with Drosophila Par-1) [30,31]. This interaction does not depend on prior phosphorylation of MARK. Localization and probably inhibition by interaction of the spacer domain with 14-3-3 (violet), after prior phosphorylation by atypical protein kinase C (aPKC; orange), which creates a 14-3-3 binding motif on MARK [32,33]. Interaction between the carboxy-terminal tail and the amino-terminal header or catalytic domain (dotted line), creating a folded and inhibited MARK molecule (proposed for the yeast homolog Kin-1) .
Timm et al. BMC Neuroscience 2008 9(Suppl 2):S9 doi:10.1186/1471-2202-9-S2-S9