MC1R Is a Potent Regulator of PTEN after UV Exposure in Melanocytes
Copyright policy )MC1R Is a Potent Regulator of PTEN after UV Exposure in Melanocytes
The individuals carrying melanocortin-1 receptor (MC1R) variants, especially those associated with red hair color, fair skin, and poor tanning ability (RHC trait), are more prone to melanoma; however, the underlying mechanism is poorly defined. Here, we report that UVB exposure triggers phosphatase and tensin homolog (PTEN) interaction with wild-type (WT), but not RHC-associated MC1R variants, which protects PTEN from WWP2-mediated degradation, leading to AKT inactivation. Strikingly, the biological consequences of the failure of MC1R variants to suppress PI3K/AKT signaling are highly context dependent. In primary melanocytes, hyperactivation of PI3K/AKT signaling leads to premature senescence; in the presence of BRAF(V600E), MC1R deficiency-induced elevated PI3K/AKT signaling drives oncogenic transformation. These studies establish the MC1R-PTEN axis as a central regulator for melanocytes' response to UVB exposure and reveal the molecular basis underlying the association between MC1R variants and melanomagenesis.
- Boston College United States
- University of Murcia Spain
- Shanghai University of Traditional Chinese Medicine China (People's Republic of)
- Ludwig Cancer Research United Kingdom
- Brigham and Women's Faulkner Hospital United States
Proto-Oncogene Proteins B-raf, 4, Blotting, Western, Melanoma, Experimental, animal cell, phosphatidylinositol 3, Real-Time Polymerase Chain Reaction, Immunoenzyme Techniques, Mice, Phosphatidylinositol 3-Kinases, genetic variability, carcinogen melanocortin 1 receptor, Animals, Humans, phosphatidylinositol 3 kinase, RNA, Messenger, Phosphorylation, Molecular Biology, Cells, Cultured, Reverse Transcriptase Polymerase Chain Reaction, article, PTEN Phosphohydrolase, in vitro, enzyme activation, Cell Biology, animal cell culture, cell fractionation, Gene Expression Regulation, 5 trisphosphate 3 phosphatase, Mutation, protein kinase B, Melanocytes, Proto-Oncogene Proteins c-akt, Receptor, Melanocortin, Type 1, Signal Transduction
Proto-Oncogene Proteins B-raf, 4, Blotting, Western, Melanoma, Experimental, animal cell, phosphatidylinositol 3, Real-Time Polymerase Chain Reaction, Immunoenzyme Techniques, Mice, Phosphatidylinositol 3-Kinases, genetic variability, carcinogen melanocortin 1 receptor, Animals, Humans, phosphatidylinositol 3 kinase, RNA, Messenger, Phosphorylation, Molecular Biology, Cells, Cultured, Reverse Transcriptase Polymerase Chain Reaction, article, PTEN Phosphohydrolase, in vitro, enzyme activation, Cell Biology, animal cell culture, cell fractionation, Gene Expression Regulation, 5 trisphosphate 3 phosphatase, Mutation, protein kinase B, Melanocytes, Proto-Oncogene Proteins c-akt, Receptor, Melanocortin, Type 1, Signal Transduction
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