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Neurodegener Dis. 2006;3(4-5):207-17.

Signaling from MARK to tau: regulation, cytoskeletal crosstalk, and pathological phosphorylation.

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Max Planck Unit for Structural Molecular Biology, Hamburg, Germany.


The hyperphosphorylation of tau is an early step in the degeneration of neurons in Alzheimer's disease and other tauopathies. Of particular importance is the phosphorylation of tau in the repeat domain which detaches tau from microtubules. This makes microtubules dynamic for their role in differentiation and neurite outgrowth, and it controls the level of tau on the microtubule surface which keeps the tracks clear for axonal transport. However, the detachment of tau from microtubules can also initiate the reactions that lead to pathological aggregation into neurofibrillary tangles. Phosphorylation of tau in the repeat domain is achieved by the kinase MARK/Par-1, a member of the calcium/calmodulin-dependent protein kinase group of kinases. In this report, we focus on the modes of MARK regulation. MARK contains several domains which offer multiple ways of regulation by posttranslational modification (e.g. phosphorylation), interactions with scaffolding proteins and subcellular targeting (e.g. 14-3-3), and interactions with other proteins. We consider in particular the interactions between MARK and other kinases, notably MARKK/TAO-1 and PAK5. MARKK (a member of the Ste20 family of kinases) activates MARK by phosphorylating it at a critical threonine residue within the activation loop. Activated MARK in turn phosphorylates tau, causes its detachment from microtubules and renders them labile. PAK5 inactivates MARK, not by phosphorylation, but by binding to the catalytic domain. PAK5 contributes to microtubule stability by preventing the MARK-induced phosphorylation of tau; conversely, PAK5 contributes to actin dynamics, presumably through the activation of cofilin, an F-actin severing protein. Thus, MARK and its regulators MARKK and PAK5 appear to mediate the crosstalk between the actin and microtubule cytoskeleton in an antagonistic fashion.

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