Protein kinase MARK/PAR-1 is required for neurite outgrowth and establishment of neuronal polarity.
Protein kinases of the microtubule affinity-regulating kinase (MARK) family were originally discovered because of their ability to phosphorylate certain sites in tau protein (KXGS motifs in the repeat domain). This type of phosphorylation is enhanced in abnormal tau from Alzheimer brain tissue and causes the detachment of tau from microtubules. MARK-related kinases (PAR-1 and KIN1) occur in various organisms and are involved in establishing and maintaining cell polarity. Herein, we report the ability of MARK2 to affect the differentiation and outgrowth of cell processes from neuroblastoma and other cell models. MARK2 phosphorylates tau protein at the KXGS motifs; this results in the detachment of tau from microtubules and their destabilization. The formation of neurites in N2a cells is blocked if MARK2 is inactivated, either by transfecting a dominant negative mutant, or by MARK2 inhibitors such as hymenialdisine. Alternatively, neurites are blocked if the target KXGS motifs on tau are rendered nonphosphorylatable by point mutations. The results suggest that MARK2 contributes to the plasticity of microtubules needed for neuronal polarity and the growth of neurites.
Biernat
Jacek
J
Max-Planck-Unit for Structural Molecular Biology, Hamburg, Germany.
Wu
Yong-Zhong
YZ
Timm
Thomas
T
Zheng-Fischhöfer
Qingyi
Q
Mandelkow
Eckhard
E
Meijer
Laurent
L
Mandelkow
Eva-Maria
EM
D020816:Amino Acid Motifs; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D002460:Cell Line; D016764:Cell Polarity; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D016501:Neurites / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000187:drug effects / Q000502:physiology*; D010880:Piperidines; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011758:Pyrroles / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism*
D001381:Azepines; D004791:Enzyme Inhibitors; D005419:Flavonoids; D010880:Piperidines; D011758:Pyrroles; D011993:Recombinant Fusion Proteins; D016875:tau Proteins; C077990:alvocidib; C107079:hymenialdisine; C105549:MARK2 protein, rat; D000071679:Glycogen Synthase Kinase 3 beta; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3