Receptor Tyrosine Kinases Activate Canonical WNT/β-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct β-Catenin Phosphorylation

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（Receptor Tyrosine Kinase, RTK）信号通路与WNT/β-连环蛋白（WNT/β-catenin）信号通路协同调控诸多生物学过程，但二者相互作用的具体机制仍有待阐明。本研究发现，FGFR2、FGFR3、EGFR及TRKA激酶可强效激活WNT/β-连环蛋白信号通路，且该激活过程不依赖PI3K/AKT通路。与之相反，该效应依赖于ERK丝裂原活化蛋白激酶（ERK MAP kinase）在WNT共受体低密度脂蛋白受体相关蛋白6（LRP6）基于高尔基体网络的成熟过程中，对其Ser1490与Thr1572位点的磷酸化修饰。该磷酸化修饰可显著增强细胞对WNT信号的响应能力。此外，FGFR2、FGFR3、EGFR及TRKA可直接对β-连环蛋白的Tyr142位点进行磷酸化修饰，该修饰已被证实可通过将β-连环蛋白从膜结合钙粘蛋白复合物中释放，提升胞质内β-连环蛋白的浓度。综上，经由ERK/LRP6通路的信号转导，以及β-连环蛋白Tyr142位点的直接磷酸化修饰，代表了各类受体酪氨酸激酶系统激活经典WNT信号通路的两种核心机制。