Sustained activation of N-WASP through phosphorylation is essential for neurite extension

Dev Cell. 2002 Nov;3(5):645-58. doi: 10.1016/s1534-5807(02)00324-6.

Abstract

Neurite extension is a key process for constructing neuronal circuits during development and remodeling of the nervous system. Here we show that Src family tyrosine kinases and proteasome degradation signals synergistically regulate N-WASP in neurite extension. Src family kinases activate N-WASP through tyrosine phosphorylation, which induces Arp2/3 complex-mediated actin polymerization. Tyrosine phosphorylation of N-WASP also initiates its degradation through ubiquitination. When neurite growth is stimulated in culture, degradation of N-WASP is markedly inhibited, leading to accumulation of the phosphorylated N-WASP. On the other hand, under culture conditions that inhibit neurite extension, but favor proliferation, the phosphorylated N-WASP is degraded rapidly. Collectively, neurite extension is regulated by the balance of N-WASP phosphorylation (activation) and degradation (inactivation), which are induced by tyrosine phosphorylation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylcysteine / analogs & derivatives*
  • Acetylcysteine / pharmacology
  • Actin-Related Protein 2
  • Actin-Related Protein 3
  • Amino Acid Sequence
  • Animals
  • COS Cells
  • Cell Line
  • Chlorocebus aethiops
  • Cysteine Endopeptidases / metabolism*
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytoskeletal Proteins / metabolism
  • Female
  • Leupeptins / pharmacology
  • Mice
  • Mice, Inbred ICR
  • Molecular Sequence Data
  • Multienzyme Complexes / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Neurites / physiology*
  • PC12 Cells
  • Phosphorylation
  • Proteasome Endopeptidase Complex
  • Proto-Oncogene Proteins / genetics
  • Proto-Oncogene Proteins / metabolism
  • Proto-Oncogene Proteins c-fyn
  • Rats
  • Spodoptera
  • Wiskott-Aldrich Syndrome Protein, Neuronal
  • cdc42 GTP-Binding Protein / metabolism
  • src-Family Kinases / metabolism*

Substances

  • Actin-Related Protein 2
  • Actin-Related Protein 3
  • Actr2 protein, mouse
  • Actr3 protein, mouse
  • Cysteine Proteinase Inhibitors
  • Cytoskeletal Proteins
  • Leupeptins
  • Multienzyme Complexes
  • Nerve Tissue Proteins
  • Proto-Oncogene Proteins
  • Wasl protein, mouse
  • Wasl protein, rat
  • Wiskott-Aldrich Syndrome Protein, Neuronal
  • lactacystin
  • Fyn protein, mouse
  • Fyn protein, rat
  • Proto-Oncogene Proteins c-fyn
  • src-Family Kinases
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex
  • cdc42 GTP-Binding Protein
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde
  • Acetylcysteine