Endosome-Localized Clathrin Adaptors AP-1 and GGA2 Support Cell Surface Expression of a Subset of RTKs for Cell Growth

Abstract

The role of Golgi/endosome-localized clathrin adaptors in the maintenance of steady-state cell surface receptor tyrosine kinases (RTKs) is not well known. Here, we show that the epidermal growth factor receptor (EGFR), an RTK, associates preferentially with both AP-1 and GGA2 in vitro. AP-1 depletion reduces the expression of EGFR protein by promoting its lysosomal degradation. Proximity ligation assays demonstrated that the interaction of EGFR with AP-1 or GGA2 occurs in Rab11-positive recycling endosomes. Western blot analysis revealed that the depletion of AP-1 or GGA2 decreased surface expression of additional RTKs, such as Erb-B4 and MET. AP-1 depletion suppressed the growth of H1975 cancer cells and normal ARPE-19 cells. AP-1 was expressed in endosomes at high levels in several cancer tissues. Collectively, these results indicate that AP-1 and GGA2 function to retrieve a subset of RTKs in recycling endosomes, thereby sustaining their cell surface expression and, consequently, cancer cell growth.