RATIONALE: G protein-coupled receptors (GPCRs) respond to diversified extracellular stimuli to modulate cellular function. Despite extensive studies investigating the regulation of single @entity31679 signaling cascades, the effects of concomitant @entity31679 activation on downstream signaling and cellular function remain unclear. OBJECTIVE: We aimed to characterize the cellular mechanism by which @entity31679 crosstalk regulates mitogen-activated protein kinase (MAPK) activation. METHODS AND RESULTS: Adrenergic receptors on cardiac fibroblasts were manipulated to examine the role of arrestin in the spatiotemporal regulation of @entity3962 MAPK signaling. We show a general mechanism in which arrestin activation by one @entity31679 is capable of regulating signaling originating from another @entity31679 . Activation of Gq coupled-receptor signaling leads to prolonged @entity1366 MAPK phosphorylation, nuclear accumulation, and cellular proliferation. Interestingly, coactivation of these receptors with the beta-adrenergic receptors induced transient @entity3963 signaling localized within the cytosol, which attenuated cell proliferation. Further studies revealed that recruitment of @entity17977 to the beta2-adrenergic receptor orchestrates the sequestration of Gq-coupled receptor-induced @entity3963 to the cytosol through direct binding of @entity3963 to arrestin. CONCLUSIONS: This is the first evidence showing that @entity17977 acts as a coordinator to integrate signals from multiple GPCRs. Our studies not only provide a novel mechanism explaining the integration of mitogenic signaling elicited by different GPCRs, but also underscore the critical role of signaling crosstalk among GPCRs in vivo.

Arrestin orchestrates crosstalk between G protein-coupled receptors to modulate the spatiotemporal activation of XXXX MAPK.

@entity17977 :: ('409', 'Gene') :: ['arrestin3'] @entity3963 :: ('5594', 'Gene') :: ['ERK'] @entity31679 :: ('441931', 'Gene') :: ['GPCR'] @entity3962 :: ('5594;5595', 'Gene') :: ['extracellular signal-regulated kinase (ERK)1/2'] @entity1366 :: ('5595;5594', 'Gene') :: ['ERK1/2']
@entity3963 :: (5594,Gene) :: ['ERK']
