E-cadherin endocytosis promotes non-canonical EGFR:STAT signalling to induce cell death and inhibit heterochromatinisation

Abstract

Signalling molecules often contribute to several signalling pathways that produce distinct transcriptional outputs and cellular phenotypes. One of the major unanswered questions in cell biology is how multiple activities of signalling molecules are coordinated in space and time in vivo. Here, we focus on the Signal Transducer and Activator of Transcription (STAT) protein as a paradigm of signalling molecules involved in several independent signalling pathways. In addition to the canonical pathways, whereby STAT is phosphorylated and activated by Janus Kinases, STAT is involved in at least two non-canonical pathways. In one pathway, STAT is activated by the Epidermal Growth Factor Receptor (EGFR) promoting apoptosis. In another, it binds the Heterochromatin Protein 1 (HP1) to enhance heterochromatin formation. Using Drosophila wing discs as an epithelial system, we demonstrate that all three STAT activities coexist in this tissue. We provide evidence that while the canonical STAT signalling is dominant over non-canonical pathways, EGFR:STAT and HP1:STAT pathways compete for the availability of unphosphorylated STAT. We also describe the role of the cell-cell adhesion protein E-cadherin in EGFR:STAT signalling. Both EGFR and STAT colocalise with E-cadherin at cell-cell junctions and on intracellular vesicles. Elevated intracellular E-cadherin promotes EGFR:STAT pathway leading to apoptosis, whereas blocking E-cadherin endocytosis prevents apoptosis induction. Altogether, we propose that E-cadherin endocytosis controls the balance between two non-canonical STAT activities in a potential tumour-suppressive mechanism - junctional disassembly in dysregulated epithelial-to-mesenchymal transitions would shift this balance towards the EGFR:STAT signalling to promote apoptosis.