Department of Anatomy, University of California, San Francisco, CA 94158-2517, USA.
Nat Cell Biol. 2010 Dec;12(12):1143-53. doi: 10.1038/ncb2118. Epub 2010 Oct 31.
Polymeric immunoglobulin A (pIgA) transcytosis, mediated by the polymeric immunoglobulin receptor (pIgR), is a central component of mucosal immunity and a model for regulation of polarized epithelial membrane traffic. Binding of pIgA to pIgR stimulates transcytosis in a process requiring Yes, a Src family tyrosine kinase (SFK). We show that Yes directly phosphorylates EGF receptor (EGFR) on liver endosomes. Injection of pIgA into rats induced EGFR phosphorylation. Similarly, in MDCK cells, pIgA treatment significantly increased phosphorylation of EGFR on various sites, subsequently activating extracellular signal-regulated protein kinase (ERK). Furthermore, we find that the Rab11 effector Rab11-FIP5 is a substrate of ERK. Knocking down Yes or Rab11-FIP5, or inhibition of the Yes-EGFR-ERK cascade, decreased pIgA-pIgR transcytosis. Finally, we demonstrate that Rab11-FIP5 phosphorylation by ERK controls Rab11a endosome distribution and pIgA-pIgR transcytosis. Our results reveal a novel Yes-EGFR-ERK-FIP5 signalling network for regulation of pIgA-pIgR transcytosis.
多聚免疫球蛋白 A（pIgA）通过多聚免疫球蛋白受体（pIgR）的转胞吞作用，是黏膜免疫的一个核心组成部分，也是调节极化上皮细胞膜运输的模型。pIgA 与 pIgR 的结合刺激转胞吞作用，这一过程需要 Yes，一种Src 家族酪氨酸激酶（SFK）。我们发现 Yes 直接在肝内体上磷酸化表皮生长因子受体（EGFR）。将 pIgA 注入大鼠体内可诱导 EGFR 磷酸化。同样，在 MDCK 细胞中，pIgA 处理显著增加了 EGFR 上各种位点的磷酸化，随后激活细胞外信号调节蛋白激酶（ERK）。此外，我们发现 Rab11 效应物 Rab11-FIP5 是 ERK 的底物。敲低 Yes 或 Rab11-FIP5，或抑制 Yes-EGFR-ERK 级联反应，均可减少 pIgA-pIgR 的转胞吞作用。最后，我们证明了 ERK 对 Rab11-FIP5 的磷酸化控制了 Rab11a 内体的分布和 pIgA-pIgR 的转胞吞作用。我们的研究结果揭示了一个新的 Yes-EGFR-ERK-FIP5 信号网络，用于调节 pIgA-pIgR 的转胞吞作用。
