Glycogen synthase kinase (GSK) 3beta directly phosphorylates Serine 212 in the regulatory loop and inhibits microtubule affinity-regulating kinase (MARK) 2.
MARK/Par-1, a kinase family with diverse functions particularly in inducing cell polarity, can phosphorylate microtubule-associated proteins in their repeat domain and cause their detachment from microtubules, and thereby microtubule destabilization. Because of its role in abnormal phosphorylation of the Tau protein in Alzheimer disease, we searched for regulatory kinases. MARK family kinases can be activated by phosphorylation of a conserved threonine (Thr-208 in MARK2), and inactivated by phosphorylation of a serine (Ser-212), both in the activation loop of the catalytic domain. Activation is achieved by the kinases MARKK/TAO1 or LKB1, although the inactivating kinase was unknown. We show here that GSK3beta serves the role of the inhibitory kinase. Because 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 Alzheimer disease.
Timm
Thomas
T
Max-Planck-Unit for Structural Molecular Biology, Notkestrasse 85, 22607 Hamburg, Germany.
Balusamy
Kiruthiga
K
Li
Xiaoyu
X
Biernat
Jacek
J
Mandelkow
Eckhard
E
Mandelkow
Eva-Maria
EM
D000091162:AMP-Activated Protein Kinase Kinases; D000544:Alzheimer Disease / Q000201:enzymology* / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004789:Enzyme Activation / Q000235:genetics; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D008870:Microtubules / Q000235:genetics / Q000378:metabolism; D016716:PC12 Cells; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D017433:Protein Structure, Secondary / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D051381:Rats; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D016875:tau Proteins; C105549:MARK2 protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D017346:Protein Serine-Threonine Kinases; C488755:Stk11 protein, rat; C115483:TAO1 protein kinase; D020930:MAP Kinase Kinase Kinases; D038362:Glycogen Synthase Kinase 3; D000091162:AMP-Activated Protein Kinase Kinases