Phosphorylation of E3 ligase Smurf1 switches its substrate preference in support of axon development

Neuron. 2011 Jan 27;69(2):231-43. doi: 10.1016/j.neuron.2010.12.021.

Abstract

Ubiquitin E3 ligases serve for ubiquitination of specific substrates, and its ligase efficacy is regulated by interacting proteins or substrate modifications. Whether and how the ligases themselves are modified by cellular signaling is unclear. Here we report that protein kinase A (PKA)-dependent phosphorylation of Smad Ubiquitin Regulatory Factor 1 (Smurf1) can switch its substrate preference between two proteins of opposing actions on axon development. Extracellular factors that promote axon formation elevated Smurf1 phosphorylation at a PKA site Thr³⁰⁶, and preventing this phosphorylation reduced axon formation in cultured hippocampal neurons and impaired polarization of cortical neurons in vivo. Thr³⁰⁶-phosphorylation changed the relative affinities of Smurf1 for its substrates, leading to reduced degradation of polarity protein Par6 and increased degradation of growth-inhibiting RhoA. Thus, PKA-dependent phosphorylation of the E3 ligase could switch its substrate preference, contributing to selective protein degradation required for localized cellular function.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Axons / physiology*
  • Axons / ultrastructure
  • Brain-Derived Neurotrophic Factor / pharmacology
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism
  • Cell Polarity
  • Cells, Cultured
  • Cyclic AMP-Dependent Protein Kinases / metabolism
  • Hippocampus / cytology
  • Neurons / cytology
  • Neurons / drug effects
  • Neurons / metabolism
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism
  • Rats
  • Rats, Sprague-Dawley
  • Signal Transduction / physiology
  • Substrate Specificity
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism

Substances

  • Brain-Derived Neurotrophic Factor
  • Carrier Proteins
  • Pard6a protein, rat
  • Smurf1 protein, rat
  • Ubiquitin-Protein Ligases
  • Stk11 protein, mouse
  • Protein-Serine-Threonine Kinases
  • Cyclic AMP-Dependent Protein Kinases
  • rhoA GTP-Binding Protein