David Samuel, Kalb Robert G
Children's Hospital of Philadelphia, Joseph Stokes Jr. Research Institute, ARC 814, 3615 Civic Center Boulevard, Philadelphia, PA 19104, USA.
FEBS Lett. 2005 Feb 28;579(6):1534-8. doi: 10.1016/j.febslet.2005.01.040.
To maintain homeostasis, cells often respond to stressful extra-cellular stimuli by new gene expression. Serum/glucocorticoid-induced kinase (SGK) is an immediate early gene whose expression is induced by a variety of extra-cellular stimuli. Here, we examine the possibility that SGK can directly phosphorylate the transcription factor cyclic AMP response element binding protein (CREB). In a cell-free context, SGK physically associates with CREB and SGK phosphorylates it on serine 133. Phospho-serine 133 is essential for stimulating the transcriptional activity of CREB. Further, we show that in a variety of cellular contexts, SGK phosphorylates CREB. Activation of receptor tyrosine kinase pathways or the phosphoinositide-dependent kinase 1 (PDK1) lead to SGK-dependent CREB phosphorylation. Hormonal stimulation of epithelial cells leads to the induction of endogenous SGK and CREB phosphorylation. A dominant-negative form of SGK blocks dexamethasone-induced CREB phosphorylation. Our studies indicate that stimulation of SGK can lead to CREB phosphorylation, suggesting that CREB-dependent gene transcription is an important link between stressful extra-cellular signals and cellular responses.
为维持体内平衡，细胞常通过新基因表达来应对细胞外应激刺激。血清/糖皮质激素诱导激酶（SGK）是一种立即早期基因，其表达受多种细胞外刺激诱导。在此，我们研究了SGK能否直接磷酸化转录因子环磷酸腺苷反应元件结合蛋白（CREB）。在无细胞环境中，SGK与CREB发生物理结合，且SGK在丝氨酸133位点对其进行磷酸化。磷酸化的丝氨酸133对于刺激CREB的转录活性至关重要。此外，我们表明在多种细胞环境中，SGK均可磷酸化CREB。受体酪氨酸激酶途径或磷酸肌醇依赖性激酶1（PDK1）的激活会导致依赖SGK的CREB磷酸化。上皮细胞的激素刺激会导致内源性SGK的诱导及CREB磷酸化。SGK的显性负性形式可阻断地塞米松诱导的CREB磷酸化。我们的研究表明，SGK的激活可导致CREB磷酸化，这表明依赖CREB的基因转录是细胞外应激信号与细胞反应之间的重要联系。
