AKAP-Lbc 增强了环 AMP 对 ERK1/2 级联的控制。
AKAP-Lbc enhances cyclic AMP control of the ERK1/2 cascade.
机构信息
Howard Hughes Medical Institute, Department of Pharmacology, University of Washington School of Medicine, 1959 Pacific Avenue NE, Seattle, WA 98195, USA.
出版信息
Nat Cell Biol. 2010 Dec;12(12):1242-9. doi: 10.1038/ncb2130. Epub 2010 Nov 21.
Abstract
Mitogen-activated protein kinase (MAPK) cascades propagate a variety of cellular activities. Processive relay of signals through RAF-MEK-ERK modulates cell growth and proliferation. Signalling through this ERK cascade is frequently amplified in cancers, and drugs such as sorafenib (which is prescribed to treat renal and hepatic carcinomas) and PLX4720 (which targets melanomas) inhibit RAF kinases. Natural factors that influence ERK1/2 signalling include the second messenger cyclic AMP. However, the mechanisms underlying this cascade have been difficult to elucidate. We demonstrate that the A-kinase-anchoring protein AKAP-Lbc and the scaffolding protein kinase suppressor of Ras (KSR-1) form the core of a signalling network that efficiently relay signals from RAF, through MEK, and on to ERK1/2. AKAP-Lbc functions as an enhancer of ERK signalling by securing RAF in the vicinity of MEK1 and synchronizing protein kinase A (PKA)-mediated phosphorylation of Ser 838 on KSR-1. This offers mechanistic insight into cAMP-responsive control of ERK signalling events.
摘要
丝裂原活化蛋白激酶（MAPK）级联反应传递各种细胞活动。RAF-MEK-ERK 信号的连续传递调节细胞生长和增殖。通过该 ERK 级联传递的信号在癌症中经常被放大，并且药物如索拉非尼（用于治疗肾和肝细胞癌）和 PLX4720（靶向黑色素瘤）抑制 RAF 激酶。影响 ERK1/2 信号的自然因素包括第二信使环 AMP。然而，该级联反应的机制一直难以阐明。我们证明 AKAP-Lbc 和支架蛋白激酶 Ras 抑制剂 1（KSR-1）作为信号网络的核心，该信号网络能够有效地将 RAF 的信号传递通过 MEK，然后传递到 ERK1/2。AKAP-Lbc 通过将 RAF 固定在 MEK1 附近并同步蛋白激酶 A（PKA）介导的 KSR-1 上 Ser838 的磷酸化，作为 ERK 信号的增强子发挥作用。这为 cAMP 响应性 ERK 信号事件的控制提供了机制上的见解。
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