Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.
PLoS One. 2012;7(4):e35826. doi: 10.1371/journal.pone.0035826. Epub 2012 Apr 27.
Receptor tyrosine kinase signaling cooperates with WNT/β-catenin signaling in regulating many biological processes, but the mechanisms of their interaction remain poorly defined. We describe a potent activation of WNT/β-catenin by FGFR2, FGFR3, EGFR and TRKA kinases, which is independent of the PI3K/AKT pathway. Instead, this phenotype depends on ERK MAP kinase-mediated phosphorylation of WNT co-receptor LRP6 at Ser1490 and Thr1572 during its Golgi network-based maturation process. This phosphorylation dramatically increases the cellular response to WNT. Moreover, FGFR2, FGFR3, EGFR and TRKA directly phosphorylate β-catenin at Tyr142, which is known to increase cytoplasmic β-catenin concentration via release of β-catenin from membranous cadherin complexes. We conclude that signaling via ERK/LRP6 pathway and direct β-catenin phosphorylation at Tyr142 represent two mechanisms used by various receptor tyrosine kinase systems to activate canonical WNT signaling.
受体酪氨酸激酶信号与 WNT/β-连环蛋白信号协同调节许多生物学过程，但它们相互作用的机制仍未完全明确。我们描述了 FGFR2、FGFR3、EGFR 和 TRKA 激酶对 WNT/β-连环蛋白的强烈激活，该激活独立于 PI3K/AKT 途径。相反，这种表型取决于 ERK MAP 激酶介导的 WNT 共受体 LRP6 在其基于高尔基体网络的成熟过程中 Ser1490 和 Thr1572 的磷酸化。这种磷酸化极大地增加了细胞对 WNT 的反应。此外，FGFR2、FGFR3、EGFR 和 TRKA 直接在 Tyr142 位点磷酸化 β-连环蛋白，众所周知，通过从膜钙粘蛋白复合物释放 β-连环蛋白，Tyr142 位点的磷酸化会增加细胞质 β-连环蛋白浓度。我们得出结论，ERK/LRP6 途径的信号转导和 Tyr142 位点的直接 β-连环蛋白磷酸化代表了各种受体酪氨酸激酶系统激活经典 WNT 信号的两种机制。
