Abstract
MC1R binds PTEN and protects it from ubiquitination upon UV exposure in melanocytes.
Major finding: MC1R binds PTEN and protects it from ubiquitination upon UV exposure in melanocytes.
Concept: MC1R variants associated with red hair, fair skin, and poor tanning do not interact with PTEN.
Impact: Some MC1R variants may increase melanoma risk because they cannot stabilize PTEN after UV exposure.
Melancortin-1 receptor (MC1R) is a melanocyte-specific G protein-coupled receptor that is activated and stimulates pigment production upon UV exposure. Naturally occurring polymorphisms in the MC1R gene lead to reduced pigment production in response to UV and are associated with red hair color (RHC), fair skin, and poor tanning ability. Individuals carrying such variants also have an increased risk of melanoma, but how MC1R-RHC variants might promote melanomagenesis is unclear. Cao and colleagues compared UV-irradiated human melanocytes expressing wild-type MC1R or MC1R-RHC variants and found that PTEN levels were reduced and AKT was activated specifically in cells expressing the MC1R-RHC variants. Upon UV exposure, wild-type MC1R physically interacted with the nonphosphorylated, active form of PTEN and protected it from WWP2-mediated ubiquitination and subsequent proteasomal degradation, thus preventing downstream AKT activation. In contrast, RHC-associated MC1R variants failed to bind and stabilize PTEN and inhibit AKT activation in response to UV exposure. Inactivation of MC1R and subsequent AKT hyperactivation in primary human melanocytes led to a premature senescence phenotype much like the oncogene-induced senescence caused by the oncogenic BRAFV600E mutation found in over half of human melanomas. However, combined inactivation of MC1R and expression of BRAF V600E in immortalized melanocytes led to robust proliferation, anchorage-independent growth, and in vivo tumor formation. Notably, the transformed phenotype could only be reversed by wild-type MC1R, but not RHC-associated MC1R variants defective in PTEN binding. In patient-derived melanoma cell lines, PTEN mutations and RHC-associated MC1R polymorphisms were largely mutually exclusive, providing further evidence that these genetic changes are functionally equivalent in melanoma. The finding that RHC-associated MC1R variants fail to inhibit AKT in UV-exposed melanocytes and can cooperate with BRAF V600E to drive melanocytic transformation provides a mechanistic explanation for the elevated risk of melanoma in individuals with decreased pigmentation.
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