Department of Biochemistry, The Rappaport Family Institute for Research in the Medical Sciences, Faculty of Medicine, Technion - Israel Institute of Technology, Haifa 31096, Israel.
Development. 2014 Jan;141(2):410-21. doi: 10.1242/dev.095984. Epub 2013 Dec 18.
Protein tyrosine kinase 7 (PTK7) is a transmembrane protein expressed in the developing Xenopus neural plate. PTK7 regulates vertebrate planar cell polarity (PCP), controlling mesodermal and neural convergent-extension (CE) cell movements, neural crest migration and neural tube closure in vertebrate embryos. Besides CE phenotypes, we now show that PTK7 protein knockdown also inhibits Wnt/β-catenin activity. Canonical Wnt signaling caudalizes the neural plate via direct transcriptional activation of the meis3 TALE-class homeobox gene, which subsequently induces neural CE. PTK7 controls meis3 gene expression to specify posterior tissue and downstream PCP activity. Furthermore, PTK7 morphants phenocopy embryos depleted for Wnt3a, LRP6 and Meis3 proteins. PTK7 protein depletion inhibits embryonic Wnt/β-catenin signaling by strongly reducing LRP6 protein levels. LRP6 protein positively modulates Wnt/β-catenin, but negatively modulates Wnt/PCP activities. The maintenance of high LRP6 protein levels by PTK7 triggers PCP inhibition. PTK7 and LRP6 proteins physically interact, suggesting that PTK7 stabilization of LRP6 protein reciprocally regulates both canonical and noncanonical Wnt activities in the embryo. We suggest a novel role for PTK7 protein as a modulator of LRP6 that negatively regulates Wnt/PCP activity.
蛋白酪氨酸激酶 7（PTK7）是一种跨膜蛋白，在发育中的非洲爪蟾神经板中表达。PTK7 调节脊椎动物平面细胞极性（PCP），控制中胚层和神经会聚延伸（CE）细胞运动、神经嵴迁移和脊椎动物胚胎神经管闭合。除了 CE 表型外，我们现在还表明，PTK7 蛋白敲低也抑制了 Wnt/β-catenin 活性。经典 Wnt 信号通过直接转录激活 meis3 TALE 类同源盒基因使神经板尾侧化，随后诱导神经 CE。PTK7 控制 meis3 基因表达以指定后组织和下游 PCP 活性。此外，PTK7 形态发生缺陷胚胎模拟了 Wnt3a、LRP6 和 Meis3 蛋白缺失的胚胎。PTK7 蛋白耗竭通过强烈降低 LRP6 蛋白水平来抑制胚胎 Wnt/β-catenin 信号。LRP6 蛋白正向调节 Wnt/β-catenin，但负向调节 Wnt/PCP 活性。PTK7 维持高 LRP6 蛋白水平触发 PCP 抑制。PTK7 和 LRP6 蛋白相互作用，表明 PTK7 稳定 LRP6 蛋白可相互调节胚胎中经典和非经典 Wnt 活性。我们提出了一种新的 PTK7 蛋白作为 LRP6 调节剂的作用，该调节剂负调节 Wnt/PCP 活性。
