Gαq-Dependent Activation of Mitogen-Activated Protein Kinase Kinase 4/c-Jun N-Terminal Kinase Cascade

Abstract

G-protein-coupled receptors (GPCRs) typically activate c-Jun N-terminal kinase (JNK) through the G protein βγ subunit (Gβγ), in a manner dependent on Rho family small GTPases, in mammalian cells. Here we show that JNK activation by the prototypic Gq-coupled α1B-adrenergic receptor is mediated by the α subunit of Gq (Gαq), not by Gβγ, using a transient transfection system in human embryonic kidney cells. JNK activation by the α1B-adrenergic receptor/Gαq was selectively mediated by mitogen-activated protein kinase kinase 4 (MKK4), but not MKK7. Also, MKK4 activation by the α1B-adrenergic receptor/Gαq required c-Src and Rho family small GTPases. Furthermore, activation of the α1B-adrenergic receptor stimulated JNK activity through Src family tyrosine kinases and Rho family small GTPases in hamster smooth muscle cells that natively express the α1B-adrenergic receptor. Together, these results suggest that the α1B-adrenergic receptor/Gαq may up-regulate JNK activity through a MKK4 pathway dependent on c-Src and Rho family small GTPases in mammalian cells.