G-Protein-Coupled Receptors Signaling to MAPK/Erk

G protein-coupled receptors (GPCRs) are activated by a wide variety of external stimuli. Upon receptor activation, the G protein exchanges GDP for GTP, causing the dissociation of the GTP-bound α and β/γ subunits and triggering diverse signaling cascades. Receptors coupled to different heterotrimeric G protein subtypes can utilize different scaffolds to activate the small G protein/ MAPK cascade, employing at least three different classes of Tyr kinases. Src family kinases are recruited following activation of PI3Kγ by β/γ subunits. They are also recruited by receptor internalization, crossactivation of receptor Tyr kinases, or by signaling through an integrin scaffold involving Pyk2 and/or FAK. GPCRs can also employ PLCβ to mediate activation of PKC and CaMKII, which can have either stimulatory or inhibitory consequences for the downstream MAPK pathway.

Selected Reviews:

• Aoki Y, Niihori T, Narumi Y, Kure S, Matsubara Y (2008) The RAS/MAPK syndromes: novel roles of the RAS pathway in human genetic disorders. Hum. Mutat. 29(8), 992–1006.
• Caunt CJ, Finch AR, Sedgley KR, McArdle CA (2006) Seven-transmembrane receptor signalling and ERK compartmentalization. Trends Endocrinol. Metab. 17(7), 276–83.
• Goldsmith ZG, Dhanasekaran DN (2007) G protein regulation of MAPK networks. Oncogene 26(22), 3122–42.
• Kim EK, Choi EJ (2010) Pathological roles of MAPK signaling pathways in human diseases. Biochim. Biophys. Acta 1802(4), 396–405.
• McKay MM, Morrison DK (2007) Integrating signals from RTKs to ERK/MAPK. Oncogene 26(22), 3113–21.

We would like to thank Prof. John Blenis, Harvard Medical School, Boston, MA, for reviewing this diagram.

created October 2002

revised October 2012