Shades of meaning: the pigment‐type switching system as a tool for discovery

Walker, Will P.; Gunn, Teresa M.

doi:10.1111/j.1755-148x.2010.00721.x

Cited by 44 publications

(43 citation statements)

References 112 publications

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“…Thus, carriers of hypomorphic MC1R variants normally display an inefficient or absent tanning response (Healy et al, 2000;Rees, 2004) and a higher risk of melanoma and non-melanoma skin cancer (Box et al, 1997;Box et al, 2001;Duffy et al, 2004;Duffy et al, 2010;Palmer et al, 2000). In keeping with this important biological role, MC1R signaling is highly regulated not only by general mechanisms such as homologous desensitization acting on most if not all GPCRs (Sánchez- Más et al, 2005a), but also by specific mechanisms restricted to the MCR subfamily of GPCRs (Barsh et al, 2000;Pérez-Oliva et al, 2009;Walker and Gunn, 2010). Previous work from our laboratory showed that whereas MC1R signaling to the cAMP pathway is downregulated by GRK2-and GRK6-dependent homologous desensitization (Sánchez- Más et al, 2005a), only GRK6 is involved in agonistpromoted receptor internalization (Sánchez-Laorden et al, 2007).…”

Section: Competitive Association Of Arrb1 and Arrb2 Isoforms With Mc1rmentioning

confidence: 99%

“…Modulation of MC1R activity is responsible for much of the normal variation in mammalian pigmentation. High MC1R activity is associated with eumelanogenesis and darker pigmentation (Ito and Wakamatsu, 2011;Rees, 2004;Robbins et al, 1993), whereas decreased or absent signaling leads to reddish pheomelanogenic pigment production (Beaumont et al, 2007;Duffy et al, 2004;Healy et al, 2000;Healy et al, 2001;Jiménez-Cervantes et al, 2001;Sánchez-Laorden et al, 2006;Walker and Gunn, 2010). Following exposure to ultraviolet radiation (UVR), MC1R also activates DNA repair and survival mechanisms (Böhm et al, 2005;Kadekaro et al, 2005;Kadekaro et al, 2010) as well as antioxidant defences (Kadekaro et al, 2012;Maresca et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Differential and competitive regulation of human melanocortin 1 receptor signaling by β-arrestin isoforms

Abrisqueta

Herráiz

Oliva

et al. 2013

Journal of Cell Science

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SummaryThe melanocortin 1 receptor (MC1R) is a G-protein-coupled receptor (GPCR) crucial for the regulation of melanocyte proliferation and differentiation. MC1R activation by melanocortin hormones triggers the cAMP pathway and stimulates the extracellular-signalregulated protein kinases ERK1 and ERK2 to promote synthesis of photoprotective eumelanin pigments, among other effects. Signaling from most GPCRs is regulated by the b-arrestin (ARRB) family of cytosolic multifunctional adaptor proteins, which mediate signal termination and endocytosis of GPCR-agonist complexes. The ubiquitously expressed non-visual b-arrestin1 (ARRB1) and b-arrestin2 (ARRB2) are highly similar but not functionally equivalent. Their role in the regulation of MC1R is unknown. Using a combination of co-immunoprecipitation, gel filtration chromatography, confocal microscopy, siRNA-mediated knockdown and functional assays, we demonstrated agonist-independent competitive interactions of ARRB1 and ARRB2 with MC1R, which might also be independent of phosphorylation of Ser/Thr residues in the C-terminus of the MC1R. The effects of ARRBs were isoform specific; ARRB2 inhibited MC1R agonist-dependent cAMP production but not ERK activation, stimulated internalization and showed prolonged co-localization with the receptor in endocytic vesicles. By contrast, ARRB1 had no effect on internalization or functional coupling, but competed with ARRB2 for binding MC1R, which might increase signaling by displacement of inhibitory ARRB2. These data suggest a new mechanism of MC1R functional regulation based on the relative expression of ARRB isoforms, with possible activatory ARRB1-dependent effects arising from partial relief of inhibitory ARRB2-MC1R interactions. Thus, competitive displacement of inhibitory ARRBs by functionally neutral ARRB isoforms might exert a paradigm-shifting signal-promoting effect to fine-tune signaling downstream of certain GPCRs.

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Section: Competitive Association Of Arrb1 and Arrb2 Isoforms With Mc1rmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Differential and competitive regulation of human melanocortin 1 receptor signaling by β-arrestin isoforms

Abrisqueta

Herráiz

Oliva

et al. 2013

Journal of Cell Science

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“…Therefore, the quantity and the ratio of eu-to pheomelanin depend primarily on the activity of tyrosinase and the presence of substrates cysteine and tyrosine in the melanosomes. Two major regulators of melanogenesis, namely the melanocortins and the Agouti protein (ASIP), control the level and activity of the tyrosinase via binding to the melanocortin 1 receptor (MC1R) (Ito and Wakamatsu 2011;Walker and Gunn 2010). Binding of melanocortins, particularly -MSH, to MC1R, induces transcription and activity of eumelanic genes such as MITF, tyrosinase, TRP1 and DCT, and therefore increases the production of black/brown eumelanin.…”

Section: Introductionmentioning

confidence: 99%

Pale and dark reddish melanic tawny owls differentially regulate the level of blood circulating POMC prohormone in relation to environmental conditions

et al. 2011

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Knowledge of the hormonal pathway controlling genotype-specific norms of reaction would shed light on the ecological factors to which each genotype is adapted. Environmentally mediated changes in the sign and magnitude of covariations between heritable melanin-based colouration and fitness components are frequent, revealing that extreme melanin-based phenotypes can display different physiological states depending on the environment. Yet, the hormonal mechanism underlying this phenomenon is poorly understood. One novel hypothesis proposes that these covariations stem from pleiotropic effects of the melanocortin system. Melanocortins are post-translationally modified bioactive peptides derived from the POMC prohormone that are involved in melanogenesis, anti-inflammation, energy homeostasis and stress responses. Thus, differential regulation of fitness components in relation to environmental factors by pale and dark melanic individuals may be due to colour-specific regulation of the POMC prohormone. Accordingly, we found that the degree of reddish melanic colouration was negatively correlated with blood circulating levels of the POMC prohormone in female tawny owls (Strix aluco) rearing a brood for which the size was experimentally reduced, but not when enlarged, and in females located in rich but not in poor territories. Our findings support the hypothesis that the widespread links between melanin-based colouration and fitness components may be mediated, at least in part, by the melanocortin system.

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“…The exact mechanism by which MGRN1 may be involved in pigment type switching has remained uncertain, although genetic studies have suggested that it may function downstream of agouti but upstream of, or at the same level as, the MC1R (7). It has also been suggested that MGRN1 may ubiquitinate MC1R to promote its internalization or lysosomal degradation (13), an observation supported by Rouzaud et al (14) who showed that the MC1R protein levels were reduced in cultured melanocytes when stimulated with ASP.…”

mentioning

confidence: 74%

The E3 Ubiquitin Ligase Mahogunin Ubiquitinates the Melanocortin 2 Receptor

2011

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Mahogunin ring fnger-1(MGRN1) encodes an E3 ubiquitin ligase and is mutated in the mahoganoid mouse. The mahoganoid mouse mutant shows similarities to the phenotype of another spontaneous mouse mutation known as mahogunin (mutation in attractin) presenting with dark coat color, spongiform neurodegeneration, and high embryonic lethality. It has long been hypothesized that MGRN1 may down-regulate the function of the melanocortin 1 receptor (MC1R) via ubiquitination or internalization because it has been shown to possess E3 ubiquitin ligase activity. However, a recent study revealed that MGRN1's role in MC1R function was independent of receptor ubiquitination and that MGRN1 negatively regulated MC1R function by competing with Gαs for receptor binding. In this study we attempted to determine whether MGRN1 is involved in the function of the melanocortin 2 receptor (MC2R). We show that MGRN1 is expressed in the zona glomerulosa and fasciculata cells of the adrenal cortex, and in transfected human embryonic kidney 293 cells it colocalizes at the cell surface with the MC2R, and coimmunoprecipitates with the MC2R. However MGRN1 did not appear to influence the cAMP-signaling function of the MC2R. In the presence of MGRN1 the MC2R is ubiquitinated and, after ACTH stimulation, evidence of multi-monoubiquitination appears. It therefore seems probable that the role of MGRN1 in the adrenal relates to the trafficking and/or degradation of the MC2R.

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Shades of meaning: the pigment‐type switching system as a tool for discovery

Cited by 44 publications

References 112 publications

Differential and competitive regulation of human melanocortin 1 receptor signaling by β-arrestin isoforms

Differential and competitive regulation of human melanocortin 1 receptor signaling by β-arrestin isoforms

Pale and dark reddish melanic tawny owls differentially regulate the level of blood circulating POMC prohormone in relation to environmental conditions

The E3 Ubiquitin Ligase Mahogunin Ubiquitinates the Melanocortin 2 Receptor

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