MC1R Is a Potent Regulator of PTEN after UV Exposure in Melanocytes

•UVB exposure triggers PTEN interaction with wild-type, but not MC1R RHC variants•WT, but not MC1R RHC variants, protect PTEN from WWP2-mediated ubiquitination•MC1R deficiency leads to the onset of premature senescence in primary melanocytes•MC1R deficiency cooperates with BRAFV600E to drive melanomagenesis

SummaryThe 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 BRAFV600E, 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.