G alpha(q) acts as an adaptor protein in protein kinase C zeta (PKCzeta)-mediated ERK5 activation by G protein-coupled receptors (GPCR).
G(q)-coupled G protein-coupled receptors (GPCR) mediate the actions of a variety of messengers that are key regulators of different cellular functions. These receptors can regulate a highly interconnected network of biochemical routes that control the activity of several members of the mitogen-activated protein kinase (MAPK) family. The ERK5 MAPK has been shown to be activated by G(q)-coupled GPCR via unknown mechanisms. We find that the atypical protein kinase C (PKCzeta), previously reported to interact with the ERK5 activator MEK5 and to be involved in epidermal growth factor-mediated ERK5 stimulation, plays a crucial role in the activation of the ERK5 pathway by G(q)-coupled GPCR. Stimulation of ERK5 by G(q)-coupled GPCR is abolished upon pharmacological inhibition of PKCzeta as well as in embryonic fibroblasts obtained from PKCzeta-deficient mice. Both PKCzeta and MEK5 associate to G alpha(q) upon activation of GPCR, thus forming a ternary complex that seems essential for the activation of ERK5. These data put forward a novel function of G alpha(q) as a scaffold protein involved in the modulation of the ERK5 cascade by GPCR that could be relevant in G(q)-mediated physiological functions.
García-Hoz
Carlota
C
Departamento de Biología Molecular, Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, 28049 Madrid, Spain.
Sánchez-Fernández
Guzmán
G
Díaz-Meco
Maria Teresa
MT
Moscat
Jorge
J
Mayor
Federico
F
Ribas
Catalina
C
D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D043802:GTP-Binding Protein alpha Subunits, Gq-G11 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D048671:MAP Kinase Kinase 5 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D008817:Mice, Mutant Strains; D048054:Mitogen-Activated Protein Kinase 7 / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism*; D041681:NIH 3T3 Cells; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D020836:Protein Structure, Quaternary; D043562:Receptors, G-Protein-Coupled / Q000235:genetics / Q000378:metabolism*; D000099221:Protein Kinase C zeta
D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D048671:MAP Kinase Kinase 5; D048054:Mitogen-Activated Protein Kinase 7; D046912:Multiprotein Complexes; D011493:Protein Kinase C; D043562:Receptors, G-Protein-Coupled; D000099221:Protein Kinase C zeta