Abstract
Signaling via a variety of G-protein-coupled receptors (GPCRs) leads to activation of nuclear factor (NF)-kappa B. Evidence exists for a signaling pathway initiated by the B2 type bradykinin receptor via G(q) activation, which leads to the sequential stimulation of phosphoinositide 3-kinase (PI3K), the serine/threonine kinase Akt, I kappa B kinases, and finally nuclear factor NF-kappa B-dependent transcription. GPCR-mediated G(q)alpha or G(13)alpha activation also potently stimulates the tyrosine kinase PYK2. In this study we tested whether G(q)alpha- and/or G(13)alpha-induced PYK2 activation contributes to GPCR-mediated NF-kappa B activation. Among the GTPase-deficient forms of G alpha tested, G(13)alpha and G(q)alpha most potently stimulated an NF-kappa B-dependent reporter gene. PYK2 activated the same reporter gene and synergized with either G(q)alpha Q209L (QL) or G(13)alpha Q226L (QL). Placing PYK2 upstream of both PI3K and Akt activation, PYK2 activated Akt through a PI3K-dependent pathway, and either a dominant negative form of Akt or the PI3K inhibitor LY294002 blocked PYK2-stimulated NF-kappa B-dependent transcription. Placing PYK2 downstream of G-protein activation, a kinase-dead form of PYK2, PYK2 (KD), blocked NF-kappa B-dependent transcription triggered by signaling through the muscarinic receptor type 1 and either G(q)alpha QL or G(13)alpha QL. PYK2 (KD) also blocked Akt activation by the same stimuli. These results indicate that PYK2 can link G-protein activation through PI3K, Akt, and I kappa B kinase to NF-kappa B activation.
Highlights
Signaling via a variety of G-protein-coupled receptors (GPCRs) leads to activation of nuclear factor (NF)-B
Evidence exists for a signaling pathway initiated by the B2 type bradykinin receptor via Gq activation, which leads to the sequential stimulation of phosphoinositide 3-kinase (PI3K), the serine/threonine kinase Akt, IB kinases, and nuclear factor NF-B-dependent transcription
PYK2 (KD) blocked Akt activation by the same stimuli. These results indicate that PYK2 can link G-protein activation through PI3K, Akt, and IB kinase to NF-B activation
Summary
Evidence exists for a signaling pathway initiated by the B2 type bradykinin receptor via Gq activation, which leads to the sequential stimulation of phosphoinositide 3-kinase (PI3K), the serine/threonine kinase Akt, IB kinases, and nuclear factor NF-B-dependent transcription. The direct effectors of G-protein activation in turn activate additional molecules including the protein kinase cascades that activate mitogen-activated protein kinases ERK1 and ERK2, p38, and stress-activated protein kinases ( referred to as Jun kinases) Through these signaling pathways G-proteincoupled receptors (GPCRs) connect extracellular stimuli to alterations in gene transcription. Because some GPCR agonists including certain chemokines can trigger increased PYK2 kinase activity [13, 14], PYK2 signaling to NF-B could provide a unifying hypothesis to explain the requirement for PYK2 and NF-B in the generation of marginal zone B cells or in recruitment to their microenvironment. We sought to examine whether PYK2 activation can lead to NF-B activation and to determine the importance of PYK2 in G-protein-mediated NF-B activation
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