title: Activation of the ERK/MAPK pathway by an isoform of rap1GAP associated with G alpha(i)
abstract: 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.
authors.affiliation: Department of Pathology, Research Institute, International Medical Center of Japan, Tokyo.
authors.forename: N
authors.initials: N
authors.lastname: Mochizuki
authors.forename: Y
authors.initials: Y
authors.lastname: Ohba
authors.forename: E
authors.initials: E
authors.lastname: Kiyokawa
authors.forename: T
authors.initials: T
authors.lastname: Kurata
authors.forename: T
authors.initials: T
authors.lastname: Murakami
authors.forename: T
authors.initials: T
authors.lastname: Ozaki
authors.forename: A
authors.initials: A
authors.lastname: Kitabatake
authors.forename: K
authors.initials: K
authors.lastname: Nagashima
authors.forename: M
authors.initials: M
authors.lastname: Matsuda
mesh_terms: D016475:3T3 Cells; D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D004268:DNA-Binding Proteins; D004789:Enzyme Activation; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D019204:GTP-Binding Proteins / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D006160:Guanosine Triphosphate / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D008969:Molecular Sequence Data; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051381:Rats; D011976:Receptors, Muscarinic / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000378:metabolism; D050807:ets-Domain Protein Elk-1; D020668:rap GTP-Binding Proteins; D020703:ras GTPase-Activating Proteins
chemical_list: D004268:DNA-Binding Proteins; C494114:Elk1 protein, rat; D020690:GTPase-Activating Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011976:Receptors, Muscarinic; D014157:Transcription Factors; D050807:ets-Domain Protein Elk-1; D020703:ras GTPase-Activating Proteins; D006160:Guanosine Triphosphate; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; C498015:GNAI2 protein, human; D051960:GTP-Binding Protein alpha Subunit, Gi2; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; C498016:Gnai2 protein, mouse; C498017:Gnai2 protein, rat; D020668:rap GTP-Binding Proteins