The Down syndrome candidate dual-specificity tyrosine phosphorylation-regulated kinase 1A phosphorylates the neurodegeneration-related septin 4

Neuroscience. 2008 Dec 2;157(3):596-605. doi: 10.1016/j.neuroscience.2008.09.034. Epub 2008 Oct 1.

Abstract

The dual-specific kinase DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) is the mammalian orthologue of the Drosophila minibrain (MNB) protein kinase and executes diverse roles in neuronal development and adult brain physiology. DYRK1A is overexpressed in Down syndrome (DS) and has recently been implicated in several neurodegenerative diseases. In an attempt to elucidate the molecular basis of its involvement in cognitive and neurodegeneration processes, we searched for novel proteins interacting with the kinase domain of DYRK1A in the adult mouse brain and identified septin 4 (SEPT4, also known as Pnutl2/CDCrel-2). SEPT4 is a member of the group III septin family of guanosine triphosphate hydrolases (GTPases), which has previously been found in neurofibrillary tangles of Alzheimer disease brains and in alpha-synuclein-positive cytoplasmic inclusions in Parkinson disease brains. In transfected mammalian cells, DYRK1A specifically interacts with and phosphorylates SEPT4. Phosphorylation of SEPT4 by DYRK1A was inhibited by harmine, which has recently been identified as the most specific inhibitor of DYRK1A. In support of a physiological relation in the brain, we found that Dyrk1A and Sept4 are co-expressed and co-localized in neocortical neurons. These findings suggest that SEPT4 is a substrate of DYRK1A kinase and thus provide a possible link for the involvement of DYRK1A in neurodegenerative processes and in DS neuropathologies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain / anatomy & histology
  • Brain / metabolism
  • Cell Line, Transformed
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism*
  • GTP Phosphohydrolases / genetics
  • GTP Phosphohydrolases / metabolism*
  • Green Fluorescent Proteins / genetics
  • Humans
  • Immunoprecipitation / methods
  • Mice
  • Mutation / genetics
  • Neurons / cytology
  • Neurons / metabolism
  • Phosphorylation / physiology
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Protein-Tyrosine Kinases / genetics
  • Protein-Tyrosine Kinases / metabolism*
  • RNA, Messenger / metabolism
  • Septins
  • Transfection / methods
  • Two-Hybrid System Techniques

Substances

  • Cytoskeletal Proteins
  • RNA, Messenger
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • Dyrk kinase
  • Protein-Tyrosine Kinases
  • Protein-Serine-Threonine Kinases
  • GTP Phosphohydrolases
  • SEPTIN4 protein, human
  • Septins