Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 289, Issue 44, Pages 30443-30458Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M114.608992
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Funding
- National Institutes of Health [CA116552, CA105489, CA99163, CA87986, CA96844, CA144027, CA127239]
- Dept. of Defense [W81WH-11-1-0167, W81XWH-07-1-0351, W81XWH-11-1-0171]
- NE DHHS [LB506-2014-01]
- Nebraska DHHS [LB606-18123-Y3]
- Nebraska Center for Nanomedicine-Center for Biomedical Research Excellence (NCN-COBRE) seed grant
- NCI Core Support Grant
- NCI Institutional Cancer Biology Training Grant [CA009476]
- Susan G. Komen Foundation for Cure postdoctoral Fellowship [KG091363]
- UNMC Faculty Diversity Scholar award
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ErbB2 overexpression drives oncogenesis in 20-30% cases of breast cancer. Oncogenic potential of ErbB2 is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation of ErbB2 recycling is incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 breast cancer cells to identify kinases whose inhibition alters the clearance of cell surface ErbB2 induced by Hsp90 inhibitor 17-AAG. Less ErbB2 clearance was observed with broad-spectrum PKC inhibitor Ro 31-8220. A similar effect was observed with Go 6976, a selective inhibitor of classical Ca2+-dependent PKCs (alpha, beta 1, beta II, and gamma). PKC activation by PMA promoted surface ErbB2 clearance but without degradation, and ErbB2 was observed to move into a juxtanuclear compartment where it colocalized with PKC-alpha and PKC-delta together with the endocytic recycling regulator Arf6. PKC-alpha knockdown impaired the juxtanuclear localization of ErbB2. ErbB2 transit to the recycling compartment was also impaired upon PKC-delta knockdown. PMA-induced Erkphosphorylation was reduced by ErbB2 inhibitor lapatinib, as well as by knockdown of PKC-delta but not that of PKC-alpha. Our results suggest that activation of PKC-alpha and -delta mediates a novel positive feedback loop by promoting ErbB2 entry into the endocytic recycling compartment, consistent with reported positive roles for these PKCs in ErbB2-mediated tumorigenesis. As the endocytic recycling compartment/pericentrion has emerged as a PKC-dependent signaling hub for G-protein-coupled receptors, our findings raise the possibility that oncogenesis by ErbB2 involves previously unexplored PKC-dependent endosomal signaling.
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