TY - JOUR
T1 - Arrestin serves as a molecular switch, linking endogenous α2-adrenergic receptor to SRC-dependent, but not SRC-independent, ERK activation
AU - Wang, Qin
AU - Lu, Roujian
AU - Zhao, Jiali
AU - Limbird, Lee E.
PY - 2006/9/8
Y1 - 2006/9/8
N2 - Our previous studies have demonstrated that neither receptor endocytosis nor arrestin is required for ERK activation by the α2- adrenergic receptor (Wang, Q., Zhao, J., Brady, A. E., Feng, J., Allen, P. B., Lefkowitz, R. J., Greengard, P., and Limbird, L. E. (2004) Science 304, 1940-1944). The present studies address whether arrestin plays a role in determining the route of α2AR-evoked ERK signaling activation, taking advantage of endogenous expression of the α2AAR subtype in mouse embryonic fibroblasts (MEFs) and the availability of MEFs without arrestin expression (derived from Arr2,3-/- mice). Our data demonstrate that the endogenous α2AAR evokes ERK phosphorylation through both a Src-dependent and a Src-independent pathway, both of which are G protein dependent and converge on the Ras-Raf-MEK pathway. Arrestin is essential to recruit Src to this process, as α2AAR- mediated ERK signaling in Arr2,3-/- MEFs does not involve Src. Stimulation of α2AAR enhances arrestin-Src interaction and promotes activation of Src. α2 agonists have similar potencies in stimulating Src-dependent and Src-independent ERK phosphorylation in wild-type and Arr2,3-/- cells, respectively. However, Src-independent α2AAR-mediated ERK stimulation has both a longer duration of activation and a more rapid translocation of pERK into the nucleus when compared with Src-dependent activation. These data not only affirm the role of arrestin as an escort for signaling molecules such as Src family kinases but also demonstrate the impact of arrestin-dependent modulation on both the temporal and spatial properties of ERK activation.
AB - Our previous studies have demonstrated that neither receptor endocytosis nor arrestin is required for ERK activation by the α2- adrenergic receptor (Wang, Q., Zhao, J., Brady, A. E., Feng, J., Allen, P. B., Lefkowitz, R. J., Greengard, P., and Limbird, L. E. (2004) Science 304, 1940-1944). The present studies address whether arrestin plays a role in determining the route of α2AR-evoked ERK signaling activation, taking advantage of endogenous expression of the α2AAR subtype in mouse embryonic fibroblasts (MEFs) and the availability of MEFs without arrestin expression (derived from Arr2,3-/- mice). Our data demonstrate that the endogenous α2AAR evokes ERK phosphorylation through both a Src-dependent and a Src-independent pathway, both of which are G protein dependent and converge on the Ras-Raf-MEK pathway. Arrestin is essential to recruit Src to this process, as α2AAR- mediated ERK signaling in Arr2,3-/- MEFs does not involve Src. Stimulation of α2AAR enhances arrestin-Src interaction and promotes activation of Src. α2 agonists have similar potencies in stimulating Src-dependent and Src-independent ERK phosphorylation in wild-type and Arr2,3-/- cells, respectively. However, Src-independent α2AAR-mediated ERK stimulation has both a longer duration of activation and a more rapid translocation of pERK into the nucleus when compared with Src-dependent activation. These data not only affirm the role of arrestin as an escort for signaling molecules such as Src family kinases but also demonstrate the impact of arrestin-dependent modulation on both the temporal and spatial properties of ERK activation.
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U2 - 10.1074/jbc.M605415200
DO - 10.1074/jbc.M605415200
M3 - Article
C2 - 16809338
AN - SCOPUS:33748749459
SN - 0021-9258
VL - 281
SP - 25948
EP - 25955
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 36
ER -