Department of Pathology, New York University Cancer Institute, Smilow Research Center, New York University School of Medicine, New York, NY, USA.
Cell Cycle. 2010 Mar 1;9(5):971-4. doi: 10.4161/cc.9.5.10914. Epub 2010 Mar 9.
F-box proteins are the substrate recognition subunits of SCF (Skp1, Cul1, F-box protein) ubiquitin ligase complexes. Skp2 is a nuclear F-box protein that targets the CDK inhibitor p27 for ubiquitin- and proteasome-dependent degradation. In G(0) and during the G(1) phase of the cell cycle, Skp2 is degraded via the APC/C(Cdh1) ubiquitin ligase to allow stabilization of p27 and inhibition of CDKs, facilitating the maintenance of the G(0)/G(1) state. APC/C(Cdh1) binds Skp2 through an N-terminal domain (amino acids 46-94 in human Skp2). It has been shown that phosphorylation of Ser64 and Ser72 in this domain dissociates Skp2 from APC/C. More recently, it has instead been proposed that phosphorylation of Skp2 on Ser72 by Akt/PKB allows Skp2 binding to Skp1, promoting the assembly of an active SCF(Skp2) ubiquitin ligase, and Skp2 relocalization/retention into the cytoplasm, promoting cell migration via an unknown mechanism. According to these reports, a Skp2 mutant in which Ser72 is substituted with Ala is unable to promote cell proliferation and loses its oncogenic potential. Given the contrasting reports, we revisited these results and conclude that phosphorylation of Skp2 on Ser72 does not control Skp2 binding to Skp1 and Cul1, has no influence on SCF(Skp2) ubiquitin ligase activity, and does not affect the subcellular localization of Skp2.
F-box 蛋白是 SCF（Skp1、Cul1、F-box 蛋白）泛素连接酶复合物的底物识别亚基。Skp2 是一种核 F-box 蛋白，可将 CDK 抑制剂 p27 靶向泛素和蛋白酶体依赖性降解。在 G0 期和细胞周期的 G1 期，Skp2 通过 APC/C（Cdh1）泛素连接酶降解，以允许 p27 的稳定和 CDK 的抑制，促进 G0/G1 状态的维持。APC/C（Cdh1）通过 Skp2 的 N 端结构域（人 Skp2 的氨基酸 46-94）与 Skp2 结合。已经表明，该结构域中 Ser64 和 Ser72 的磷酸化使 Skp2 与 APC/C 解离。最近，相反的观点是 Akt/PKB 对 Skp2 的 Ser72 磷酸化允许 Skp2 与 Skp1 结合，促进活性 SCF（Skp2）泛素连接酶的组装，以及 Skp2 向细胞质的重新定位/保留，通过未知机制促进细胞迁移。根据这些报道，Ser72 被 Ala 取代的 Skp2 突变体不能促进细胞增殖并丧失其致癌潜能。鉴于这些相互矛盾的报道，我们重新审视了这些结果，并得出结论，Skp2 的 Ser72 磷酸化不能控制 Skp2 与 Skp1 和 Cul1 的结合，对 SCF（Skp2）泛素连接酶活性没有影响，也不影响 Skp2 的亚细胞定位。
