Crosstalk between KDEL receptor and EGF receptor mediates cell proliferation and migration via STAT3 signaling

Abstract

Abstract Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase that hosts complex signaling events and plays diverse roles in a variety of cellular processes. Secreted ER chaperones are capable of activating EGFR and its downstream transcription factor, STAT3. However, the molecular mechanism of these ER proteins triggering EGFR signaling is largely unknown. In this study, we identify KDEL receptor (KDELR) as a cell surface receptor for secreted ER chaperones and a co-receptor for EGFR. Prior to ligand addition, KDELR spontaneously oligomerizes and constantly undergoes recycling near the plasma membrane. Upon ligand binding, the interactions of KDELR with itself and with EGFR increase rapidly, leading to augmented internalization of KDELR and tyrosine phosphorylation in the C-terminus of EGFR. STAT3, which binds the phosphorylated tyrosine motif on EGFR, is subsequently activated by EGFR and induces transcription of genes relevant to cell proliferation and migration. Taken together, our results suggest that secreted ER chaperones bind surface-expressed KDELR and transactivates EGFR-STAT3 signaling pathway.