title: MC1R is a potent regulator of PTEN after UV exposure in melanocytes.
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 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.
authors: Department of Dermatology, Boston University School of Medicine, 609 Albany Street, Boston, MA 02118, USA.
authors: Juxiang
authors: J
authors: Cao
authors: Lixin
authors: L
authors: Wan
authors: Elke
authors: E
authors: Hacker
authors: Xiangpeng
authors: X
authors: Dai
authors: Stefania
authors: S
authors: Lenna
authors: Celia
authors: C
authors: Jimenez-Cervantes
authors: Yongjun
authors: Y
authors: Wang
authors: Nick R
authors: NR
authors: Leslie
authors: George X
authors: GX
authors: Xu
authors: Hans R
authors: HR
authors: Widlund
authors: Byungwoo
authors: B
authors: Ryu
authors: Rhoda M
authors: RM
authors: Alani
authors: Ken
authors: K
authors: Dutton-Regester
authors: Colin R
authors: CR
authors: Goding
authors: Nicholas K
authors: NK
authors: Hayward
authors: Wenyi
authors: W
authors: Wei
authors: Rutao
authors: R
authors: Cui
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000528:radiation effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D008544:Melanocytes / Q000378:metabolism* / Q000528:radiation effects; D008546:Melanoma, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D012880:Skin Pigmentation / Q000502:physiology* / Q000528:radiation effects; D014466:Ultraviolet Rays; D000521:alpha-MSH / Q000235:genetics / Q000378:metabolism
chemical_list: D012333:RNA, Messenger; D044102:Receptor, Melanocortin, Type 1; D000521:alpha-MSH; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human
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