A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells

摘要: ErbB2 overexpression drives oncogenesis in 20–30% cases of breast cancer. Oncogenic potential is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation recycling incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 cancer cells identify kinases whose inhibition alters the clearance cell surface induced by Hsp90 17-AAG. Less was observed with broad-spectrum PKC Ro 31-8220. A similar effect Go 6976, selective classical Ca2+-dependent PKCs (α, β1, βII, γ). activation PMA promoted but without degradation, move juxtanuclear compartment where it colocalized PKC-α PKC-δ together regulator Arf6. knockdown impaired localization ErbB2. transit also upon knockdown. PMA-induced Erk phosphorylation reduced lapatinib, as well not that PKC-α. Our results suggest -δ mediates novel positive feedback loop promoting entry compartment, consistent reported roles for these ErbB2-mediated tumorigenesis. As compartment/pericentrion has emerged PKC-dependent signaling hub G-protein-coupled receptors, our findings raise possibility involves previously unexplored endosomal signaling.