MARK/Par-1, a kinase family with diverse functions, especially in inducing cell polarity, can phosphorylate microtubule-associated proteins in their repeat domain, cause their detachment from microtubules and thereby microtubule destabilization. Because of its role in abnormal phosphorylation of Tau protein in Alzheimer's disease we searched for regulatory kinases. MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr208 in MARK2), and inactivated by phosphorylation of a serine (Ser212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, but the inactivating kinase was not known. We show here that GSK3beta serves the role of the inhibitory kinase. Since GSK3beta can also phosphorylate Tau at sites outside the repeat domain, the activation of GSK3beta and concomitant inactivation of MARK can shift the pattern of pathological phosphorylation of Tau protein in AD.