MC1R is a potent regulator of PTEN after UV exposure in melanocytes

Juxiang Cao, Lixin Wan, Elke Hacker, Xiangpeng Dai, Stefania Lenna, Celia Jimenez-Cervantes, Yongjun Wang, NickR Leslie, GeorgeX Xu, HansR Widlund, Byungwoo Ryu, RhodaM Alani, Ken Dutton-Regester, ColinR Goding, NicholasK Hayward, Wenyi Wei, Rutao Cui

Research output: Contribution to journalArticlepeer-review

Abstract

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 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.

Original languageEnglish (US)
Pages (from-to)409-422
Number of pages14
JournalMolecular Cell
Volume51
Issue number4
DOIs
StatePublished - Aug 22 2013
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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