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β-Arrestin, originally identified as a protein that inhibits heterotrimeric guanine nucleotide–binding protein (G protein) coupling to cognate seven-transmembrane receptors [(7TMRs), also known as G protein–coupled receptors (GPCRs)], is currently being appreciated as a positive signaling mediator for various cell surface receptors. Activation of mitogen-activated protein kinases (MAPKs), especially extracellular signal regulated kinases 1 and 2 (ERK1/2), is a hallmark of intracellular signaling resulting from stimulation of various growth factor receptors, as well as 7TMRs. The resulting ERK activity can occur through multiple parallel or converging mechanisms. Using human embryonic kidney 293 (HEK-293) cells as a model system and utilizing RNA interference technology, two distinct pathways of angiotensin II-mediated ERK activation have been uncovered: (i) a G protein–dependent pathway that produces a transient activation of nuclear ERK and (ii) a β-arrestin–dependent pathway that leads to sustained activation of ERK that is localized to the cytosol and endosomes. The spatial and temporal segregation of ERK activated by G protein and β-arrestin pathways suggests that the physiological consequences may be different, and thus ligands that selectively stimulate or inhibit one of these pathways may be therapeutically valuable.