Microtubule affinity-regulating kinase 2 functions downstream of the PAR-3/PAR-6/atypical PKC complex in regulating hippocampal neuronal polarity

Proc Natl Acad Sci U S A. 2006 May 30;103(22):8534-9. doi: 10.1073/pnas.0509955103. Epub 2006 May 22.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Carrier Proteins / metabolism*
  • Cell Line
  • Cell Polarity
  • Hippocampus / cytology*
  • Hippocampus / enzymology*
  • Humans
  • Mitogen-Activated Protein Kinases / metabolism
  • Mutation / genetics
  • Nerve Tissue Proteins
  • Neurons / cytology
  • Neurons / enzymology*
  • Phosphorylation
  • Protein Binding
  • Protein Kinase C / metabolism*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proteins / metabolism*
  • Rats
  • tau Proteins / metabolism

Substances

  • Carrier Proteins
  • Nerve Tissue Proteins
  • Pard3 protein, rat
  • Proteins
  • tau Proteins
  • MARK2 protein, rat
  • Protein-Serine-Threonine Kinases
  • PKC-3 protein
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases