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Papel deL PKC[zeta] en la estimulación de ERK5 por GPCRs acoplados a proteínas Gq y su repercusión en hipertrofia cardiaca

AutorGarcía-Hoz Jiménez, Carlota
DirectorMayor Menéndez, Federico ; Ribas Núñez, Catalina
Palabras claveProteínas G
Hipertrofia cardiaca
Fecha de publicación2008
EditorUniversidad Autónoma de Madrid
ResumenIn this work we show that PKCζ plays a key role in the activation of the ERK5 pathway by Gqcoupled GPCR in epithelial cells and in cardiomyocytes as well as in the induction of cardiac hypertrophy by agonists acting through Gq-coupled GPCR such as angiotensin II. Several lines of evidence support the notion that a functional interaction between Gαq and PKCζ mediates the triggering of the ERK5 cascade by Gq-coupled GPCR. First, ERK5 stimulation by carbachol or angiotensin II does not appear to require the activity of EGF-Receptors (EGFR) or cytosolic tyrosine kinases, known to participate in ERK5 activation in response to different mitogens, thus suggesting that potential GPCR/EGFR transactivation mechanisms are not involved. Second, overexpression of a constitutively active Gαq subunit mutant promotes “per se” ERK5 stimulation, independently of its ability to interact with the classical Gαq effector PLCβ. Third, Gαq (and not other Gα subunits) associates with PKCζ in cells, and co-immunoprecipitation of these endogenous proteins can be promoted upon Gq-coupled GPCR activation. Moreover, a direct Gαq/PKCζ interaction can be observed using purified proteins. Fourth, Gαq, PKCζ and MEK5 (the upstream ERK5 activator) are present in the same multimolecular complex as assessed by co-immunoprecipitation experiments. Interestingly, Gαq also directly interacts with MEK5, suggesting a scaffold role for this G protein subunit in the stimulation of this pathway. Finally, stimulation of ERK5 by Gq-coupled GPCR is blocked by PKCζ pharmacological inhibitors and absent in MEFs or cardiomyocytes derived from PKCζ-deficient mice. Thus, these data put forward PKCζ as a novel Gαq effector required for ERK5 activation by Gqcoupled GPCR. Moreover, the finding that PKCζ-deficient mice do not develop angiotensin-induced cardiac hypertrophy indicates an important physiopathological role for this novel Gαq/PKCζ/ERK5 signaling axis. In sum, the novel Gαq/PKCζ/ERK5 signal transduction route presented in this study may help to better understand the mechanisms underlying GPCR-induced cardiac hypertrophy and in the design of new therapeutic strategies. On the other hand, it opens new avenues to investigate the potential role of this pathway in other cell types and physiological processes.
DescripciónTesis doctoral inédita. Universidad Autónoma de Madrid, Facultad de Ciencias, Departamento de Biología Molecular. Fecha de lectura: 27-06-08
Aparece en las colecciones: (CBM) Tesis
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