Institut de Recherche en Immunologie et Cancérologie, Université de Montréal, Montreal, QC, Canada.
Cell Cycle. 2010 Mar 1;9(5):975-9. doi: 10.4161/cc.9.5.10915. Epub 2010 Mar 9.
Skp2 is the substrate binding subunit of the SCF(Skp2) ubiquitin ligase, which plays a key role in the regulation of cell cycle progression. The activity of Skp2 is regulated by the APC(Cdh1), which targets Skp2 for degradation in early G(1) and prevent premature S phase entry. Overexpression of Skp2 leads to dysregulation of the cell cycle and is commonly observed in human cancers. We have previously shown that Skp2 is phosphorylated on Ser64 and Ser72 in vivo, and that these modifications regulate its stability. Recently, two studies have proposed a role for Ser72 phosphorylation in the cytosolic relocalization of Skp2 and in the assembly and activity of SCF(Skp2) ubiquitin ligase complex. We have revisited this question and analyzed the impact of Ser72 phosphorylation site mutations on the biological activity and subcellular localization of Skp2. We show here that phosphorylation of 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 in a panel of cell lines.
Skp2 是 Skp2 泛素连接酶的底物结合亚基，在细胞周期进程的调控中起着关键作用。Skp2 的活性受 APC(Cdh1)调节，APC(Cdh1)在早期 G1 期将 Skp2 靶向降解，以防止过早进入 S 期。Skp2 的过表达导致细胞周期失调，在人类癌症中常见。我们之前已经表明，Skp2 在体内的 Ser64 和 Ser72 上发生磷酸化，这些修饰调节其稳定性。最近，两项研究提出 Ser72 磷酸化在 Skp2 的细胞质重定位以及 SCF(Skp2)泛素连接酶复合物的组装和活性中的作用。我们重新研究了这个问题，并分析了 Ser72 磷酸化位点突变对 Skp2 的生物学活性和亚细胞定位的影响。我们在这里表明，Ser72 的磷酸化不控制 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 在一系列细胞系中的亚细胞定位。
