Sasaki Takanori, Kojima Hirotada, Kishimoto Rikiya, Ikeda Ayu, Kunimoto Hiroyuki, Nakajima Koich
Department of Immunology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka 545-8585, Japan.
Mol Cell. 2006 Oct 6;24(1):63-75. doi: 10.1016/j.molcel.2006.08.005.
c-Fos is regulated by phosphorylation and multiple turnover mechanisms. We found that c-Fos was ubiquitylated in the cytoplasm during IL-6/gp130 stimulation under MEK inhibition and sought the mechanisms involved in the regulation. We show that sustained ERK5 activity and the E3 ligase UBR1 regulate the stability and subcellular localization of c-Fos. UBR1, rapidly induced by STAT3, interacts with and ubiquitylates c-Fos in the cytoplasm for its accelerated degradation. ERK5 inhibits the nuclear export of c-Fos by phosphorylating Thr232 in the c-Fos NES(221-233) and disrupts the interaction of c-Fos with UBR1 by phosphorylating Ser32. Moreover, UBR1 depletion in HeLa cells, which constitutively express UBR1 at a high level, enhances both c-Fos expression and cell growth, whereas ERK5 depletion reduces both of them. Interestingly, an NES mutant of c-Fos, but not wild-type, substitutes ERK5 activity for HeLa cell proliferation. Thus, this spatiotemporal regulation of c-Fos by ERK5 and UBR1 is critical for the regulation of c-Fos/AP-1.
c-Fos受磷酸化和多种周转机制调控。我们发现，在MEK抑制下白细胞介素-6/gp130刺激期间，c-Fos在细胞质中发生泛素化，并探寻其中涉及的调控机制。我们发现，持续的ERK5活性和E3连接酶UBR1调节c-Fos的稳定性和亚细胞定位。由STAT3快速诱导的UBR1在细胞质中与c-Fos相互作用并使其泛素化，从而加速其降解。ERK5通过磷酸化c-Fos核输出信号（221-233）中的苏氨酸232来抑制c-Fos的核输出，并通过磷酸化丝氨酸32破坏c-Fos与UBR1的相互作用。此外，在高表达UBR1的HeLa细胞中敲低UBR1可增强c-Fos表达和细胞生长，而敲低ERK5则会降低二者。有趣的是，c-Fos的核输出信号突变体而非野生型可替代ERK5活性以促进HeLa细胞增殖。因此，ERK5和UBR1对c-Fos的这种时空调控对c-Fos/AP-1的调控至关重要。
