Gu C, Ma Y C, Benjamin J, Littman D, Chao M V, Huang X Y
Graduate Program of Cell Biology and Genetics, Graduate Program of Physiology, Biophysics and Molecular Medicine, and the Department of Physiology, Cornell University Medical College, New York, New York 10021, USA.
J Biol Chem. 2000 Jul 7;275(27):20726-33. doi: 10.1074/jbc.M000152200.
Stimulation of beta-adrenergic receptor normally results in signaling by the heterotrimeric G protein G(s), leading to the activation of adenylyl cyclase, production of cAMP, and activation of cAMP-dependent protein kinase (PKA). Here we report that cell death of thymocytes can be induced after stimulation of beta-adrenergic receptor, or by addition of exogenous cAMP. Apoptotic cell death in both cases was observed with the appearance of terminal deoxynucleotidyl transferase-mediated UTP end labeling reactivity and the activation of caspase-3 in S49 T cells. Using thymocytes deficient in either Galpha(s) or PKA, we find that engagement of beta-adrenergic receptors initiated a Galpha(s)-dependent, PKA-independent pathway leading to apoptosis. This alternative pathway involves Src family tyrosine kinase Lck. Furthermore, we show that Lck protein kinase activity can be directly stimulated by purified Galpha(s). Our data reveal a new signaling pathway for Galpha(s), distinct from the classical PKA pathway, that accounts for the apoptotic action of beta-adrenergic receptors.
β-肾上腺素能受体的刺激通常会导致异源三聚体G蛋白G(s)发出信号，从而激活腺苷酸环化酶、产生环磷酸腺苷（cAMP）并激活cAMP依赖性蛋白激酶（PKA）。在此我们报告，β-肾上腺素能受体受到刺激后，或添加外源性cAMP后，均可诱导胸腺细胞死亡。在这两种情况下，均可观察到凋亡性细胞死亡，表现为末端脱氧核苷酸转移酶介导的UTP末端标记反应性的出现以及S49 T细胞中caspase-3的激活。利用缺乏Gα(s)或PKA的胸腺细胞，我们发现β-肾上腺素能受体的激活启动了一条依赖Gα(s)、不依赖PKA的凋亡途径。这条替代途径涉及Src家族酪氨酸激酶Lck。此外，我们表明纯化的Gα(s)可直接刺激Lck蛋白激酶活性。我们的数据揭示了一条与经典PKA途径不同的Gα(s)新信号通路，该通路解释了β-肾上腺素能受体的凋亡作用。
