STAR particles promise a novel topical drug delivery system

IGF-1 receptor (IGF1R) signaling promotes keratinocyte proliferation, migration, and survival. However, the mechanism of IGF1R endocytosis in normal keratinocytes remains unclear. Confocal, super resolution struc-tured illumination microscopy, total internal reflection fluorescence microscopy, and coimmunoprecipitation studies reveal that IGF1R associates with flotillin-1 (Flot-1), which currently has no known role in normal re-ceptor tyrosine kinase endocytosis, under basal conditions in monolayer keratinocyte cultures. Ligand stim-ulation of IGF1R promotes its clathrin-dependent endocytosis, mediated by two distinct adaptors, Flot-1 in noncaveolar lipid rafts and the AP2A1/2 complex in clathrin vesicles. Concurrent, but not individual, short hairpin RNA knockdown of FLOT1/2 and AP2A1/2 reduced IGF1R association with clathrin, internalization, and pathway activation by more than 50% (of phosphorylated IGF1R, phosphorylated protein kinase B, and phos-phorylated MAPK kinase), suggesting the complementarity of these two adaptor-specific pathways. The Flot-1 pathway is more responsive to low IGF-1 concentrations, whereas the AP2A1/2 pathway predominates at higher IGF-1 concentrations. Selective association of IGF1R-Flot-1-clathrin with Rab4, but IGF1R-AP2A1/2-clathrin with Rab11, implicates Flot-1 as the adaptor for faster recycling and AP2A1/2 as the adaptor for slower IGF1R recycling. These dual pathways, particularly flotillin-dependent, clathrin-mediated endocytosis, provide a new avenue for drug targeting in disorders with aberrant regulation of IGF1R signaling. Journal of Investigative Dermatology (2020) 140, 1743-1752; doi:10.1016/j.jid.2020.01.015