Department of Developmental and Regenerative Biology, Mount Sinai School of Medicine, New York, New York 10029, USA.
Genes Dev. 2010 Oct 1;24(19):2157-68. doi: 10.1101/gad.1961010. Epub 2010 Sep 13.
Abelson (Abl) family tyrosine kinases have been implicated in cell morphogenesis, adhesion, motility, and oncogenesis. Using a candidate approach for genes involved in planar cell polarity (PCP) signaling, we identified Drosophila Abl (dAbl) as a modulator of Frizzled(Fz)/PCP signaling. We demonstrate that dAbl positively regulates the Fz/Dishevelled (Dsh) PCP pathway without affecting canonical Wnt/Wg-Fz signaling. Genetic dissection suggests that Abl functions via Fz/Dsh signaling in photoreceptor R3 specification, a well-established Fz-PCP signaling readout. Molecular analysis shows that dAbl binds and phosphorylates Dsh on Tyr473 within the DEP domain. This phosphorylation event on Dsh is functionally critical, as the equivalent DshY473F mutant is nonfunctional in PCP signaling and stable membrane association, although it rescues canonical Wnt signaling. Strikingly, mouse embryonic fibroblasts (MEFs) deficient for Abl1 and Abl2/Arg genes also show reduced Dvl2 phosphorylation as compared with control MEFs, and this correlates with a change in subcellular localization of endogenous Dvl2. As in Drosophila, such Abl-deficient MEFs show no change in canonical Wnt signaling. Taken together, our results argue for a conserved role of Abl family members in the positive regulation of Dsh activity toward Fz-Dsh/PCP signaling by Dsh phosphorylation.
艾伯森（Abl）家族酪氨酸激酶参与细胞形态发生、黏附、运动和肿瘤发生。我们使用候选方法鉴定参与平面细胞极性（PCP）信号的基因，发现果蝇 Abl（dAbl）是 Frizzled（Fz）/PCP 信号的调节剂。我们证明 dAbl 正向调节 Fz/Dishevelled（Dsh）PCP 途径，而不影响经典 Wnt/Wg-Fz 信号。遗传分析表明，Abl 通过 Fz/Dsh 信号在光感受器 R3 特化中发挥作用，这是一个已建立的 Fz-PCP 信号读出。分子分析表明，dAbl 结合并在 DEP 结构域内的 Tyr473 上磷酸化 Dsh。Dsh 上的这种磷酸化事件在功能上是关键的，因为等效的 DshY473F 突变体在 PCP 信号和稳定的膜结合中无功能，尽管它可以挽救经典的 Wnt 信号。引人注目的是，与对照 MEFs 相比， Abl1 和 Abl2/Arg 基因缺失的小鼠胚胎成纤维细胞（MEFs）也显示 Dvl2 磷酸化减少，这与内源性 Dvl2 的亚细胞定位变化相关。与果蝇一样， Abl 缺陷型 MEFs 中经典 Wnt 信号没有变化。总之，我们的结果表明 Abl 家族成员在通过 Dsh 磷酸化正向调节 Dsh 对 Fz-Dsh/PCP 信号的活性方面具有保守作用。
