Heesom K J, Gampel A, Mellor H, Denton R M
University of Bristol, Department of Biochemistry, School of Medical Sciences, University Walk, BS8 1TD, Bristol, United Kingdom.
Curr Biol. 2001 Sep 4;11(17):1374-9. doi: 10.1016/s0960-9822(01)00422-5.
A fundamental control point in the regulation of the initiation of protein synthesis is the formation of the eukaryotic initiation factor 4F (eIF-4F) complex. The formation of this complex depends upon the availability of the mRNA cap binding protein, eIF-4E, which is sequestered away from the translational machinery by the tight association of eIF-4E binding proteins (4E-BPs). Phosphorylation of 4E-BP1 is critical in causing its dissociation from eIF-4E, leaving 4E available to form translationally active eIF-4F complexes, switching on mRNA translation. In this report, we provide the first evidence that the phosphorylation of 4E-BP1 increases during mitosis and identify Ser-65 and Thr-70 as phosphorylated sites. Phosphorylation of Thr-70 has been implicated in the regulation of 4E-BP1 function, but the kinase phosphorylating this site was unknown. We show that the cyclin-dependent kinase, cdc2, phosphorylates 4E-BP1 at Thr-70 and that phosphorylation of this site is permissive for Ser-65 phosphorylation. Crucially, the increased phosphorylation of 4E-BP1 during mitosis results in its complete dissociation from eIF-4E.
蛋白质合成起始调控中的一个基本控制点是真核生物起始因子4F（eIF - 4F）复合物的形成。该复合物的形成取决于mRNA帽结合蛋白eIF - 4E的可用性，而eIF - 4E结合蛋白（4E - BPs）紧密结合将其隔离于翻译机制之外。4E - BP1的磷酸化对于使其与eIF - 4E解离至关重要，从而使eIF - 4E可用于形成具有翻译活性的eIF - 4F复合物，开启mRNA翻译。在本报告中，我们提供了首个证据，即4E - BP1的磷酸化在有丝分裂期间增加，并确定Ser - 65和Thr - 70为磷酸化位点。Thr - 70的磷酸化与4E - BP1功能的调节有关，但磷酸化该位点的激酶尚不清楚。我们表明，细胞周期蛋白依赖性激酶cdc2在Thr - 70位点磷酸化4E - BP1，并且该位点的磷酸化允许Ser - 65磷酸化。至关重要的是，有丝分裂期间4E - BP1磷酸化增加导致其与eIF - 4E完全解离。
