Downregulation of ErbB2 by Perturbing its Endocytic Recycling

摘要

About 25% of breast cancers arise from the overexpression of ErbB2, which increases its cell surface level on mammary cells to result in enhanced mitogenic signaling. Recent evidence suggests that endocytic recycling contributes to the high surface level of ErbB2, but unlike all other currently known intracellular transport pathways, the conventional mechanism of protein sorting by coat proteins is thought not to play a significant role in endocytic recycling. However, in light of emerging evidence that this prevailing view might not be correct, we had originally proposed to gain insight into whether ErbB2 recycling follows the conventional mechanism of cargo sorting by testing whether it possessed recycling sorting signal(s), which are recognized by distinct coat proteins for sorting into different transport pathways. Since then, we have identified a novel clathrin coat complex that contains ACAP1 to mediate all examples of recycling that we have examined. This finding has led us to revise our originally proposed experiments, and we show that a pool of internalized ErbB2 colocalize and interact with the novel clathrin coat complex that we have recently identified for endocytic recycling. Significantly, our findings also suggest a more direct approach in the future to study whether ErbB2 recycling modulates its signaling.