Torres M A, Eldar-Finkelman H, Krebs E G, Moon R T
Howard Hughes Medical Institute and Department of Pharmacology, University of Washington School of Medicine, Seattle, Washington, USA.
Mol Cell Biol. 1999 Feb;19(2):1427-37. doi: 10.1128/MCB.19.2.1427.
beta-Catenin is a multifunctional protein that binds cadherins at the plasma membrane, HMG box transcription factors in the nucleus, and several cytoplasmic proteins that are involved in regulating its stability. In developing embryos and in some human cancers, the accumulation of beta-catenin in the cytoplasm and subsequently the nuclei of cells may be regulated by the Wnt-1 signaling cascade and by glycogen synthase kinase 3 (GSK-3). This has increased interest in regulators of both GSK-3 and beta-catenin. Searching for kinase activities able to phosphorylate the conserved, inhibitory-regulatory GSK-3 residue serine 9, we found p90(rsk) to be a potential upstream regulator of GSK-3. Overexpression of p90(rsk) in Xenopus embryos leads to increased steady-state levels of total beta-catenin but not of the free soluble protein. Instead, p90(rsk) overexpression increases the levels of beta-catenin in a cell fraction containing membrane-associated cadherins. Consistent with the lack of elevation of free beta-catenin levels, ectopic p90(rsk) was unable to rescue dorsal cell fate in embryos ventralized by UV irradiation. We show that p90(rsk) is a downstream target of fibroblast growth factor (FGF) signaling during early Xenopus development, since ectopic FGF signaling activates both endogenous and overexpressed p90(rsk). Moreover, overexpression of a dominant negative FGF receptor, which blocks endogenous FGF signaling, leads to decreased p90(rsk) kinase activity. Finally, we report that FGF inhibits endogenous GSK-3 activity in Xenopus embryos. We hypothesize that FGF and p90(rsk) play heretofore unsuspected roles in modulating GSK-3 and beta-catenin.
β-连环蛋白是一种多功能蛋白质，它在质膜上与钙黏着蛋白结合，在细胞核中与HMG盒转录因子结合，还与几种参与调节其稳定性的细胞质蛋白结合。在发育中的胚胎以及某些人类癌症中，β-连环蛋白在细胞质中以及随后在细胞核中的积累可能受Wnt-1信号级联反应和糖原合酶激酶3（GSK-3）的调节。这使得人们对GSK-3和β-连环蛋白的调节因子的兴趣增加。在寻找能够磷酸化保守的、具有抑制调节作用的GSK-3残基丝氨酸9的激酶活性时，我们发现p90（rsk）是GSK-3的潜在上游调节因子。在非洲爪蟾胚胎中过表达p90（rsk）会导致总β-连环蛋白的稳态水平升高，但游离可溶性蛋白的水平不会升高。相反，p90（rsk）过表达会增加含有膜相关钙黏着蛋白的细胞组分中β-连环蛋白的水平。与游离β-连环蛋白水平未升高一致，异位表达的p90（rsk）无法挽救因紫外线照射而腹化的胚胎中的背侧细胞命运。我们表明，在非洲爪蟾早期发育过程中，p90（rsk）是成纤维细胞生长因子（FGF）信号的下游靶点，因为异位FGF信号会激活内源性和过表达的p90（rsk）。此外，过表达一种显性负性FGF受体，它会阻断内源性FGF信号，导致p90（rsk）激酶活性降低。最后，我们报告FGF在非洲爪蟾胚胎中抑制内源性GSK-3活性。我们假设FGF和p90（rsk）在调节GSK-3和β-连环蛋白方面发挥了迄今为止未被怀疑的作用。
