A kinase cascade leading to Rab11-FIP5 controls transcytosis of the polymeric immunoglobulin receptor

Polymeric immunoglobulin A (plgA) transcytosis, mediated by the polymeric immunoglobulin receptor (plgR), is a central component of mucosal immunity and a model for regulation of polarized epithelial membrane traffic. Binding of plgA to plgR 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 plgA into rats induced EGFR phosphorylation. Similarly, in MDCK cells, plgA 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 plgA-plgR transcytosis. Finally, we demonstrate that Rab11-FIP5 phosphorylation by ERK controls Rab11a endosome distribution and plgA-plgR transcytosis. Our results reveal a novel Yes-EGFR-ERK-FIP5 signalling network for regulation of plgA-plgR transcytosis.