G Protein-regulated inducer of neurite outgrowth (GRIN) modulates Sprouty protein repression of mitogen-activated protein kinase (MAPK) activation by growth factor stimulation

J Biol Chem. 2012 Apr 20;287(17):13674-85. doi: 10.1074/jbc.M111.320705. Epub 2012 Mar 1.


Gα(o/i) interacts directly with GRIN (G protein-regulated inducer of neurite outgrowth). Using the yeast two-hybrid system, we identified Sprouty2 as an interacting partner of GRIN. Gα(o) and Sprouty2 bind to overlapping regions of GRIN, thus competing for GRIN binding. Imaging experiments demonstrated that Gα(o) expression promoted GRIN translocation to the plasma membrane, whereas Sprouty2 expression failed to do so. Given the role of Sprouty2 in the regulation of growth factor-mediated MAPK activation, we examined the contribution of the GRIN-Sprouty2 interaction to CB1 cannabinoid receptor regulation of FGF receptor signaling. In Neuro-2A cells, a system that expresses all of the components endogenously, modulation of GRIN levels led to regulation of MAPK activation. Overexpression of GRIN potentiated FGF activation of MAPK and decreased tyrosine phosphorylation of Sprouty2. Pretreatment with G(o/i)-coupled CB1 receptor agonist attenuated subsequent FGF activation of MAPK. Decreased expression of GRIN both diminished FGF activation of MAPK and blocked CB1R attenuation of MAPK activation. These observations indicate that Gα(o) interacts with GRIN and outcompetes GRIN from bound Sprouty. Free Sprouty then in turn inhibits growth factor signaling. Thus, here we present a novel mechanism of how G(o/i)-coupled receptors can inhibit growth factor signaling to MAPK.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Brain / metabolism
  • Carrier Proteins / metabolism*
  • Cell Differentiation
  • Cell Line, Tumor
  • Gene Expression Regulation*
  • Gene Library
  • HEK293 Cells
  • Humans
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • MAP Kinase Signaling System / physiology*
  • Membrane Proteins / metabolism*
  • Mice
  • Nerve Tissue Proteins / metabolism*
  • Neurons / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases
  • Protein Structure, Tertiary
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Signal Transduction
  • Tyrosine / chemistry


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • GRIN1 protein, human
  • Gprin1 protein, mouse
  • Intercellular Signaling Peptides and Proteins
  • Intracellular Signaling Peptides and Proteins
  • Membrane Proteins
  • Nerve Tissue Proteins
  • Receptors, N-Methyl-D-Aspartate
  • SPRY2 protein, human
  • Tyrosine
  • Protein Serine-Threonine Kinases
  • Spry2 protein, mouse