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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.

Original publication

DOI

10.1016/j.molcel.2013.08.010

Type

Journal article

Journal

Mol Cell

Publication Date

22/08/2013

Volume

51

Pages

409 - 422

Keywords

Animals, Blotting, Western, Cells, Cultured, Gene Expression Regulation, Humans, Immunoenzyme Techniques, Melanocytes, Melanoma, Experimental, Mice, Mutation, PTEN Phosphohydrolase, Phosphatidylinositol 3-Kinases, Phosphorylation, Proto-Oncogene Proteins B-raf, Proto-Oncogene Proteins c-akt, RNA, Messenger, Real-Time Polymerase Chain Reaction, Receptor, Melanocortin, Type 1, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Skin Pigmentation, Ultraviolet Rays, alpha-MSH