Division of Microbiology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Laboratory of Animal Resources, Center for Disease Biology and Integrative Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-0033, Japan.
Nat Commun. 2016 Sep 21;7:12887. doi: 10.1038/ncomms12887.
Evolutionally conserved Wnt, Hedgehog (Hh) and Notch morphogen pathways play essential roles in the development, homeostasis and pathogenesis of multicellular organisms. Nevertheless, mechanisms that intracellularly coordinate these signal inputs remain poorly understood. Here we found that parafibromin, a component of the PAF complex, competitively interacts with β-catenin and Gli1, thereby potentiating transactivation of Wnt- and Hh-target genes in a mutually exclusive manner. Parafibromin also binds to the Notch intracellular domain (NICD), enabling concerted activation of Wnt- and Notch-target genes. The transcriptional platform function of parafibromin is potentiated by tyrosine dephosphorylation, mediated by SHP2 phosphatase, while it is attenuated by tyrosine phosphorylation, mediated by PTK6 kinase. Consequently, acute loss of parafibromin in mice disorganizes the normal epithelial architecture of the intestine, which requires coordinated activation/inactivation of Wnt, Hh and/or Notch signalling. Parafibromin integrates and converts signals conveyed by these morphogen pathways into appropriate transcriptional outputs in a tyrosine phosphorylation/dephosphorylation-regulated manner.
进化保守的 Wnt、Hedgehog (Hh) 和 Notch 形态发生素途径在多细胞生物的发育、稳态和发病机制中发挥着重要作用。然而，细胞内协调这些信号输入的机制仍知之甚少。在这里，我们发现 parafibromin（PAF 复合物的一个组成部分）竞争性地与 β-catenin 和 Gli1 相互作用，从而以相互排斥的方式增强 Wnt 和 Hh 靶基因的转录激活。Parafibromin 还与 Notch 细胞内结构域（NICD）结合，从而能够协调 Wnt 和 Notch 靶基因的激活。由 SHP2 磷酸酶介导的酪氨酸去磷酸化增强了 parafibromin 的转录平台功能，而由 PTK6 激酶介导的酪氨酸磷酸化则减弱了其功能。因此，小鼠中 parafibromin 的急性缺失会破坏肠道的正常上皮结构，这需要协调 Wnt、Hh 和/或 Notch 信号的激活/失活。Parafibromin 以酪氨酸磷酸化/去磷酸化调节的方式整合并转换这些形态发生素途径传递的信号，转化为适当的转录输出。
