GRASP-1 is a neuronal scaffold protein for the JNK signaling pathway

FEBS Lett. 2007 Sep 18;581(23):4403-10. doi: 10.1016/j.febslet.2007.08.008. Epub 2007 Aug 14.

Abstract

GRASP-1 is a neuronally enriched protein that interacts with the AMPA-type glutamate receptor/GRIP complex. GRASP-1 can be cleaved by Caspase-3 in both normal and ischemic brains although the functional significance of this cleavage remains elusive. We investigated signal transduction pathways that might lie downstream of GRASP-1 and found that GRASP-1 potently activates JNK pathway signaling, with no effect on ERK signaling. Such JNK pathway activating activity requires binding of GRASP-1 to both JNK and the upstream JNK pathway activator MEKK-1. Furthermore, mutations that prevent Caspase 3-cleavage of GRASP-1 dramatically inhibit the JNK pathway activating activity of GRASP-1, suggesting a novel link between Caspase-3 activation and JNK pathway signaling. These results suggest that GRASP-1 serves as a scaffold protein to facilitate MEKK-1 activation of JNK signaling in neurons.

Publication types

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

MeSH terms

  • Binding Sites / genetics
  • Carrier Proteins / genetics
  • Carrier Proteins / metabolism*
  • Carrier Proteins / physiology
  • Caspase 3 / metabolism
  • Cell Line
  • Extracellular Signal-Regulated MAP Kinases / genetics
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Immunoprecipitation
  • JNK Mitogen-Activated Protein Kinases / genetics
  • JNK Mitogen-Activated Protein Kinases / metabolism*
  • MAP Kinase Kinase Kinase 1 / genetics
  • MAP Kinase Kinase Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 8 / genetics
  • Mitogen-Activated Protein Kinase 8 / metabolism
  • Mutation
  • Signal Transduction / genetics
  • Signal Transduction / physiology*
  • Transfection

Substances

  • Carrier Proteins
  • GRIPAP1 protein, human
  • Extracellular Signal-Regulated MAP Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Mitogen-Activated Protein Kinase 8
  • MAP Kinase Kinase Kinase 1
  • MAP3K1 protein, human
  • Caspase 3