Multifaceted control of E-cadherin dynamics by the Adaptor Protein Complex 1 during epithelial morphogenesis

Abstract

Intracellular trafficking regulates the distribution of transmembrane proteins including the key determinants of epithelial polarity and adhesion. The Adaptor Protein 1 (AP-1) complex is the key regulator of vesicle sorting, which binds many specific cargos. We examined roles of the AP-1 complex in epithelial morphogenesis, using the Drosophila wing as a paradigm. We found that AP-1 knockdown leads to ectopic tissue folding, which is consistent with the observed defects in integrin targeting to the basal cell-extracellular matrix adhesion sites. This occurs concurrently with an integrin-independent induction of cell death, which counteracts elevated proliferation and prevents hyperplasia. We discovered a distinct pool of AP-1, which localizes at the subapical Adherens Junctions. Upon AP-1 knockdown, E-cadherin is hyperinternalized from these junctions and becomes enriched at the Golgi and recycling endosomes. We then provide evidence that E-cadherin hyperinternalization acts upstream of cell death in a potential tumour-suppressive mechanism. Simultaneously, cells compensate for elevated internalization of E-cadherin by increasing its expression to maintain cell-cell adhesion.Author SummaryThe epithelium is one of the four types of tissues found in animals and is essential for the normal development and maintenance of multicellular organisms. In this tissue, the adhesion protein E-cadherin helps keep cells together and facilitates the coordination of their behaviours. E-cadherin is highly dynamic and undergoes constant turnover by intracellular trafficking machinery. Here, we describe the contributions of one of the core components of intracellular trafficking, the AP-1 complex to E-cadherin dynamics. Using epithelial cells from Drosophila melanogaster, we discover that the AP-1 complex limits E-cadherin internalization from the plasma membrane, which is consistent with the localization of a distinct pool of the AP-1 complex at the sites of E-cadherin cell-cell adhesion. We also show that increased E-cadherin internalization triggers programmed cell death, preventing the tissue from hyperplastic overgrowth in a potential tumour-suppressive mechanism. At the same time, cells compensate for the reduction in the membrane presentation of E-cadherin by increasing its expression, therefore protecting tissue integrity.