Tyrosine kinases in activation of the MAP kinase cascade by G-protein-coupled receptors

Abstract

The mitogen-activated protein kinase (MAPK) signalling cascade is a prominent cellular pathway used by many growth factors, hormones and neurotransmitters to regulate physiological responses. Although activation of the MAPK pathway by receptors with tyrosine kinase activity is well defined, the mechanism used by heterotrimeric G-protein-coupled receptors to activate this pathway is less clear. Here we show that in cells deficient in the Src-related tyrosine kinase Lyn, stimulation of MAPK kinase and MARPK by Gq-coupled m1 muscarinic acetylcholine receptors (mAChR) is blocked, whereas Gi-coupled m2 mAChR-mediated stimulation is unaffected. In cells deficient in the tyrosine kinase Syk, both m1 and m2 mAChRs failed to stimulate MAPK kinase and MAPK. This result indicates that Syk is essential for the Gi-coupled pathway and that Lyn and Syk are necessary for the Gq-coupled pathway.