Fang X, Yu S X, Lu Y, Bast R C, Woodgett J R, Mills G B
Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Proc Natl Acad Sci U S A. 2000 Oct 24;97(22):11960-5. doi: 10.1073/pnas.220413597.
Glycogen synthase kinase 3 (GSK-3) is implicated in multiple biological processes including metabolism, gene expression, cell fate determination, proliferation, and survival. GSK-3 activity is inhibited through phosphorylation of serine 21 in GSK-3 alpha and serine 9 in GSK-3 beta. These serine residues of GSK-3 have been previously identified as targets of protein kinase B (PKB/Akt), a serine/threonine kinase located downstream of phosphatidylinositol 3-kinase. Here, we show that serine 21 in GSK-3 alpha and serine 9 in GSK-3 beta are also physiological substrates of cAMP-dependent protein kinase A. Protein kinase A physically associates with, phosphorylates, and inactivates both isoforms of GSK-3. The results indicate that depending on the stimulatory context, the activity of GSK-3 can be modulated either by growth factors that work through the phosphatidylinositol 3-kinase-protein kinase B cascade or by hormonal stimulation of G protein-coupled receptors that link to changes in intracellular cAMP levels.
糖原合酶激酶3（GSK-3）参与多种生物学过程，包括代谢、基因表达、细胞命运决定、增殖和存活。GSK-3的活性通过GSK-3α的丝氨酸21和GSK-3β的丝氨酸9磷酸化而受到抑制。GSK-3的这些丝氨酸残基先前已被确定为蛋白激酶B（PKB/Akt）的作用靶点，PKB/Akt是一种位于磷脂酰肌醇3激酶下游的丝氨酸/苏氨酸激酶。在此，我们表明GSK-3α的丝氨酸21和GSK-3β的丝氨酸9也是环磷酸腺苷依赖性蛋白激酶A的生理底物。蛋白激酶A与GSK-3的两种同工型发生物理结合、使其磷酸化并使其失活。结果表明，根据刺激环境的不同，GSK-3的活性可以通过磷脂酰肌醇3激酶-蛋白激酶B级联反应的生长因子或通过与细胞内cAMP水平变化相关的G蛋白偶联受体的激素刺激来调节。
