Section of Molecular Cytology, Swammerdam Institute for Life Sciences, University of Amsterdam, Amsterdam, the Netherlands.
Van Leeuwenhoek Centre for Advanced Microscopy, University of Amsterdam, Amsterdam, the Netherlands.
PLoS One. 2020 Jan 21;15(1):e0227435. doi: 10.1371/journal.pone.0227435. eCollection 2020.
Wnt/ß-catenin signalling is crucial for maintaining the balance between cell proliferation and differentiation, both during tissue morphogenesis and in tissue maintenance throughout postnatal life. Whereas the signalling activities of the core Wnt/ß-catenin pathway components are understood in great detail, far less is known about the precise role and regulation of the many different modulators of Wnt/ß-catenin signalling that have been identified to date. Here we describe TMEM98, a putative transmembrane protein of unknown function, as an interaction partner and regulator of the GSK3-binding protein FRAT2. We show that TMEM98 reduces FRAT2 protein levels and, accordingly, inhibits the FRAT2-mediated induction of ß-catenin/TCF signalling. We also characterize the intracellular trafficking of TMEM98 in more detail and show that it is recycled between the plasma membrane and the Golgi. Together, our findings not only reveal a new layer of regulation for Wnt/ß-catenin signalling, but also a new biological activity for TMEM98.
Wnt/β-catenin 信号通路对于维持细胞增殖和分化之间的平衡至关重要，无论是在组织形态发生过程中，还是在出生后的整个组织维持过程中都是如此。尽管核心 Wnt/β-catenin 途径成分的信号转导活性已经得到了深入的了解，但迄今为止，人们对已鉴定出的许多不同的 Wnt/β-catenin 信号转导调节剂的确切作用和调控机制知之甚少。在这里，我们将 TMEM98 描述为一个假定的具有未知功能的跨膜蛋白，它是 GSK3 结合蛋白 FRAT2 的相互作用伙伴和调节剂。我们表明，TMEM98 降低了 FRAT2 蛋白水平，并相应地抑制了 FRAT2 介导的β-catenin/TCF 信号的诱导。我们还更详细地描述了 TMEM98 的细胞内运输，并表明它在质膜和高尔基体之间循环。总之，我们的研究结果不仅揭示了 Wnt/β-catenin 信号通路的一个新的调控层次，也揭示了 TMEM98 的一个新的生物学活性。
