Microtubule affinity-regulating kinase 2 functions downstream of the PAR-3/PAR-6/atypical PKC complex in regulating hippocampal neuronal polarity.
The PAR-3/PAR-6/atypical PKC (aPKC) complex is required for axon-dendrite specification of hippocampal neurons. However, the downstream effectors of this complex are not well defined. In this article, we report a role for microtubule affinity-regulating kinase (MARK)/PAR-1 in axon-dendrite specification. Knocking down MARK2 expression with small interfering RNAs induced formation of multiple axon-like neurites and promoted axon outgrowth. Ectopic expression of MARK2 caused phosphorylation of tau (S262) and led to loss of axons, and this phenotype was rescued by expression of PAR-3, PAR-6, and aPKC. In contrast, the polarity defects caused by an MARK2 mutant (T595A), which is not responsive to aPKC, were not rescued by the PAR-3/PAR-6/aPKC complex. Moreover, polarity was abrogated in neurons overexpressing a mutant of MARK2 with a deleted kinase domain but an intact aPKC-binding domain. Finally, suppression of MARK2 rescued the polarity defects induced by a dominant-negative aPKC mutant. These results suggest that MARK2 is involved in neuronal polarization and functions downstream of the PAR-3/PAR-6/aPKC complex. We propose that aPKC in complex with PAR-3/PAR-6 negatively regulates MARK(s), which in turn causes dephosphorylation of microtubule-associated proteins, such as tau, leading to the assembly of microtubules and elongation of axons.
Chen
Y M
YM
Institute of Neuroscience and Key Laboratory of Neurobiology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China.
Wang
Q J
QJ
Hu
H S
HS
Yu
P C
PC
Zhu
J
J
Drewes
G
G
Piwnica-Worms
H
H
Luo
Z G
ZG
D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D002460:Cell Line; D016764:Cell Polarity; D006624:Hippocampus / Q000166:cytology* / Q000201:enzymology*; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000201:enzymology*; D010766:Phosphorylation; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D011506:Proteins / Q000378:metabolism*; D051381:Rats; D016875:tau Proteins / Q000378:metabolism
D002352:Carrier Proteins; D009419:Nerve Tissue Proteins; C472451:Pard3 protein, rat; D011506:Proteins; D016875:tau Proteins; C105549:MARK2 protein, rat; D017346:Protein Serine-Threonine Kinases; C115015:PKC-3 protein; D011493:Protein Kinase C; D020928:Mitogen-Activated Protein Kinases