F A model for the PIPKIγi5-LAPTM4B pathway in EGFR trafficking. Hrs is an established key regulator of EGFR intraluminal sorting. LAPTM4B, by promoting Nedd4‐mediated Hrs ubiquitination, inhibits the recognition of ubiquitinatedEGFR by Hrs and therefore inhibits EGFR intraluminal sorting and lysosomal degradation. PIPKIγi5 directly binds to LAPTM4B and antagonizes the function of LAPTM4B in EGFR sorting by generating PtdIns(4,5) P2 signals and recruiting SNX5. 