The metastasis suppressor NDRG1 down-regulates the epidermal growth factor receptor via a lysosomal mechanism by up-regulating mitogen-inducible gene 6
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Kovacevic, Zaklina
Richardson, Des R
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Abstract
The metastasis suppressor, N-Myc downstream-regulated gene-1 (NDRG1) inhibits a plethora of oncogenic signaling pathways by down-regulating the epidermal growth factor receptor (EGFR). Herein, we examined the mechanism involved in NDRG1-mediated EGFR down-regulation. NDRG1 overexpression potently increased the levels of mitogen-inducible gene 6 (MIG6), which inhibits EGFR and facilitates its lysosomal processing and degradation. Conversely, silencing NDRG1 in multiple human cancer cell types decreased MIG6 expression, demonstrating the regulatory role of NDRG1. Further, NDRG1 overexpression facilitated MIG6 –EGFR association in the cytoplasm, possibly explaining the significantly (p <0.001) increased half-life of MIG6 from 1.6 0.2 h under control conditions to 7.9 0.4 h after NDRG1 overexpression. The increased MIG6 levels enhanced EGFR co-localization with the late endosome/lysosomal marker, lysosomal-associated membrane protein 2 (LAMP2). An increase in EGFR levels after MIG6 silencing was particularly apparent when NDRG1 was overexpressed, suggesting a role for MIG6 in NDRG1-mediated down-regulation of EGFR. Silencing phosphatase and tensin homolog (PTEN), which facilitates early to late endosome maturation, decreased MIG6, and also increased EGFR levels in both the presence and absence of NDRG1 overexpression. These results suggest a role for PTEN in regulating MIG6 expression. Anti-tumor drugs of the di-2-pyridylketone thiosemicarbazone class that activate NDRG1 expression also potently increased MIG6 and induced its cytosolic co-localization with NDRG1. This was accompanied by a decrease in activated and total EGFR levels and its redistribution to late endosomes/lysosomes. In conclusion, NDRG1 promotes EGFR down-regulation through the EGFR inhibitor MIG6, which leads to late endosomal/lysosomal processing of EGFR.
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Journal of Biological Chemistry
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294
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11
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© 2019 Menezes et al. Published under exclusive license by The American Society for Biochemistry and Molecular Biology, Inc. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License, which permits unrestricted, non-commercial use, distribution and reproduction in any medium, providing that the work is properly cited.
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Chemical sciences
Biological sciences
Biomedical and clinical sciences
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Life Sciences & Biomedicine
Biochemistry & Molecular Biology
anti-cancer drug
molecular pharmacology
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Menezes, SV; Kovacevic, Z; Richardson, DR, The metastasis suppressor NDRG1 down-regulates the epidermal growth factor receptor via a lysosomal mechanism by up-regulating mitogen-inducible gene 6, Journal of Biological Chemistry, 2019, 294 (11), pp. 4045-4064