Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with G alpha(i)

Nature. 1999 Aug 26;400(6747):891-4. doi: 10.1038/23738.


Many receptors for neuropeptides and hormones are coupled with the heterotrimeric G(i) protein, which activates the p42/44 mitogen-activated protein kinase (ERK/MAPK) cascade through both the alpha- and betagamma-subunits of G(i). The betagamma-subunit activates the ERK/MAPK cascade through tyrosine kinase. Constitutively active G(alpha)i2 (gip2) isolated from adrenal and ovarian tumours transforms Rat-1 fibroblasts and also activates the ERK/MAPK cascade by an unknown mechanism. The ERK/MAPK pathway is activated by Ras, and is inhibited when the low-molecular-mass GTP-binding protein Rap1 antagonizes Ras function. Here we show that a novel isoform of Rapl GTPase-activating protein, called rap1GAPII, binds specifically to the alpha-subunits of the G(i) family of heterotrimeric G-proteins. Stimulation of the G(i)-coupled m2-muscarinic receptor translocates rap1GAPII from the cytosol to the membrane and decreases the amount of GTP-bound Rap1. This decrease in GTP-bound Rap1 activates ERK/MAPK. Thus, the alpha-subunit of G(i) activates the Ras-ERK/MAPK mitogenic pathway by membrane recruitment of rap1GAPII and reduction of GTP-bound Rap1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3T3 Cells
  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism*
  • Cell Line
  • Cell Membrane / metabolism
  • Cytosol / metabolism
  • DNA-Binding Proteins*
  • Enzyme Activation
  • GTP Phosphohydrolases / metabolism*
  • GTP-Binding Protein alpha Subunit, Gi2
  • GTP-Binding Protein alpha Subunits, Gi-Go*
  • GTP-Binding Proteins / metabolism*
  • GTPase-Activating Proteins
  • Guanosine Triphosphate / metabolism
  • HeLa Cells
  • Humans
  • Jurkat Cells
  • Mice
  • Mitogen-Activated Protein Kinase 1 / metabolism
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases*
  • Molecular Sequence Data
  • Proteins / metabolism
  • Proto-Oncogene Proteins / metabolism*
  • Rats
  • Receptors, Muscarinic / metabolism
  • Signal Transduction
  • Transcription Factors / metabolism
  • ets-Domain Protein Elk-1
  • rap GTP-Binding Proteins
  • ras GTPase-Activating Proteins


  • DNA-Binding Proteins
  • Elk1 protein, rat
  • GTPase-Activating Proteins
  • Proteins
  • Proto-Oncogene Proteins
  • Receptors, Muscarinic
  • Transcription Factors
  • ets-Domain Protein Elk-1
  • ras GTPase-Activating Proteins
  • Guanosine Triphosphate
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • GTP Phosphohydrolases
  • GTP-Binding Proteins
  • GNAI2 protein, human
  • GTP-Binding Protein alpha Subunit, Gi2
  • GTP-Binding Protein alpha Subunits, Gi-Go
  • Gnai2 protein, mouse
  • Gnai2 protein, rat
  • rap GTP-Binding Proteins

Associated data

  • GENBANK/AB003930