Abstract
Several polarity proteins, including Scribble (Scrb) have been implicated in control of vesicle traffic, and in particular the endocytosis of E-cadherin, but through unknown mechanisms. We now show that depletion of Scrb enhances endocytosis of E-cadherin by weakening the E-cadherin-p120catenin interaction. Unexpectedly, however, the internalized E-cadherin is not degraded but accumulates in the Golgi apparatus. Silencing p120-catenin causes degradation of E-cadherin in lysosomes, but degradation is blocked by the co-depletion of Scrb, which diverts the internalized E-cadherin to the Golgi. Loss of Scrb also enhances E-cadherin binding to retromer components, and retromer is required for Golgi accumulation of Scrb, and E-cadherin stability. These data identify a novel and unanticipated function for Scrb in blocking retromer-mediated diversion of E-cadherin to the Golgi. They provide evidence that polarity proteins can modify the intracellular itinerary for endocytosed membrane proteins.
Highlights
Cell polarity is intimately related to vesicle sorting, which ensures the delivery to and removal from the appropriate membrane proteins to the correct territories on the cell surface, and maintains the distinct properties and functions of these territories
Scrb binds to the C-terminus of the TSH receptor and over-expression of Scrb can inhibit thyroid stimulating hormone receptor (TSHR) endocytosis, through a bPIX-GIT1-ARF6 pathway [9]
We have found that Scrb is required for intercellular adhesion through Ecadherin, but through a mechanism independent of bPIX [17]
Summary
Cell polarity is intimately related to vesicle sorting, which ensures the delivery to and removal from the appropriate membrane proteins to the correct territories on the cell surface, and maintains the distinct properties and functions of these territories. In MDCK epithelial cells grown in culture, Scrb is required for normal intercellular adhesion [17]. When these cells are depleted of Scrb, they appear more fibroblastic. They spread over a larger surface area and cortical actin rings are replaced by numerous stress fibers [17]. These effects are independent of b-Pix or of changes in Rac-GTP. MDCK cells lacking Scrb are unable to attach to a surface coated with the extracellular domain of E-cadherin, suggesting that Scrb is required to promote E-cadherin-mediated cell-cell adhesion [17]
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