TY - JOUR
T1 - MC1R is a potent regulator of PTEN after UV exposure in melanocytes
AU - Cao, Juxiang
AU - Wan, Lixin
AU - Hacker, Elke
AU - Dai, Xiangpeng
AU - Lenna, Stefania
AU - Jimenez-Cervantes, Celia
AU - Wang, Yongjun
AU - Leslie, NickR
AU - Xu, GeorgeX
AU - Widlund, HansR
AU - Ryu, Byungwoo
AU - Alani, RhodaM
AU - Dutton-Regester, Ken
AU - Goding, ColinR
AU - Hayward, NicholasK
AU - Wei, Wenyi
AU - Cui, Rutao
PY - 2013/8/22
Y1 - 2013/8/22
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84882657764&partnerID=8YFLogxK
U2 - 10.1016/j.molcel.2013.08.010
DO - 10.1016/j.molcel.2013.08.010
M3 - Article
C2 - 23973372
AN - SCOPUS:84882657764
SN - 1097-2765
VL - 51
SP - 409
EP - 422
JO - Molecular Cell
JF - Molecular Cell
IS - 4
ER -