Investigating the regulation of brain-specific kinases 1 and 2 by phosphorylation

J Biol Chem. 2008 May 30;283(22):14946-54. doi: 10.1074/jbc.M710381200. Epub 2008 Mar 13.


Brain-specific kinases 1 and 2 (BRSK1/2) are AMP-activated protein kinase (AMPK)-related kinases that are highly expressed in mammalian forebrain. Studies using transgenic animal models have implicated a role for these kinases in the establishment of neuronal polarity. BRSK1 and BRSK2 are activated by phosphorylation of a threonine residue in the T-loop activation segment of the kinase domain. In vitro studies have demonstrated that LKB1, an upstream kinase in the AMPK cascade, can catalyze this phosphorylation. However, to date, a detailed comparative analysis of the molecular regulation of BRSK1/2 has not been undertaken. Here we present evidence that excludes another upstream kinase in the AMPK cascade, Ca(2+)/calmodulin-dependent protein kinase kinase beta, from a role in activating BRSK1/2. We show that equivalent mutations in the ubiquitin-associated domains of the BRSK isoforms produce differential effects on the activation of BRSK1 and BRSK2. Contrary to previous reports, activation of cAMP-dependent protein kinase does not affect BRSK1 or BRSK2 activity in mammalian cells. Furthermore, stimuli that activate AMPK had no effect on BRSK1/2. Finally, we provide evidence suggesting that protein phosphatase 2C is a likely candidate for catalyzing the dephosphorylation and inactivation of BRSK1/2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinase Kinases
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1
  • Cell Line
  • Enzyme Activation / physiology
  • Gene Expression Regulation, Enzymologic / physiology
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Isoenzymes / genetics
  • Isoenzymes / metabolism
  • Mutation
  • Phosphoprotein Phosphatases / genetics
  • Phosphoprotein Phosphatases / metabolism*
  • Phosphorylation
  • Prosencephalon / enzymology
  • Protein Kinases / genetics
  • Protein Kinases / metabolism
  • Protein Phosphatase 2C
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Structure, Tertiary / physiology
  • Rabbits


  • Intracellular Signaling Peptides and Proteins
  • Isoenzymes
  • Protein Kinases
  • BRSK1 protein, human
  • Brsk2 protein, human
  • Protein Serine-Threonine Kinases
  • STK11 protein, human
  • Calcium-Calmodulin-Dependent Protein Kinase Type 1
  • AMP-Activated Protein Kinase Kinases
  • PPM1A protein, human
  • PPM1B protein, human
  • PPM1G protein, human
  • Phosphoprotein Phosphatases
  • Protein Phosphatase 2C