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Src and Fyn define a new signaling cascade activated by canonical and non-canonical Wnt ligands and required for gene transcription and cell invasion
Cellular and Molecular Life Sciences ( IF 8 ) Pub Date : 2019-07-16 , DOI: 10.1007/s00018-019-03221-2
Aida Villarroel , Beatriz del Valle-Pérez , Guillem Fuertes , Josué Curto , Neus Ontiveros , Antonio Garcia de Herreros , Mireia Duñach

Abstract

Wnt ligands signal through canonical or non-canonical signaling pathways. Although both routes share common elements, such as the Fz2 receptor, they differ in the co-receptor and in many of the final responses; for instance, whereas canonical Wnts increase β-catenin stability, non-canonical ligands downregulate it. However, both types of ligands stimulate tumor cell invasion. We show here that both the canonical Wnt3a and the non-canonical Wnt5a stimulate Fz2 tyrosine phosphorylation, Fyn binding to Fz2, Fyn activation and Fyn-dependent Stat3 phosphorylation. Wnt3a and Wnt5a require Src for Fz2 tyrosine phosphorylation; Src binds to canonical and non-canonical co-receptors (LRP5/6 and Ror2, respectively) and is activated by Wnt3a and Wnt5a. This Fz2/Fyn/Stat3 branch is incompatible with the classical Fz2/Dvl2 pathway as shown by experiments of over-expression or depletion. Fyn is necessary for transcription of genes associated with invasiveness, such as Snail1, and for activation of cell invasion by both Wnt ligands. Our results extend the knowledge about canonical Wnt pathways, demonstrating additional roles for Fyn in this pathway and describing how this protein kinase is activated by both canonical and non-canonical Wnts.



中文翻译:

Src和Fyn定义了一个新的信号传导级联,该信号级联由规范性和非规范性Wnt配体激活,是基因转录和细胞入侵所必需的

抽象的

Wnt配体通过规范或非规范的信号通路进行信号传递。尽管这两种途径共有相同的元件,例如Fz2受体,但它们在共同受体和许多最终反应中却有所不同。例如,虽然经典Wnt增加了β-catenin的稳定性,但非经典配体却下调了它的稳定性。然而,两种类型的配体均刺激肿瘤细胞侵袭。我们在这里显示经典Wnt3a和非经典Wnt5a刺激Fz2酪氨酸磷酸化,Fyn绑定到Fz2,Fyn激活和Fyn依赖于Stat3磷酸化。Wnt3a和Wnt5a需要Src才能使Fz2酪氨酸磷酸化;Src结合到规范和非规范的共受体(分别为LRP5 / 6和Ror2),并被Wnt3a和Wnt5a激活。Fz2 / Fyn / Stat3分支与经典Fz2 / Dvl2途径不兼容,如过度表达或耗竭实验所示。Fyn对于转录与侵袭性相关的基因(例如Snail1)以及两个Wnt配体激活细胞侵袭都是必需的。我们的结果扩展了有关经典Wnt途径的知识,证明了Fyn在该途径中的其他作用,并描述了该蛋白激酶如何被经典Wnt和非经典Wnt激活。

更新日期:2020-03-06
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