Transcriptional co-activator regulates melanocyte differentiation and oncogenesis by integrating cAMP and MAPK/ERK pathways

Ostojić, Jelena; Yoon, Young-Sil; Sonntag, Tim; Nguyen, Billy; Vaughan, Joan; Shokhirev, Maxim N.; Montminy, Marc

doi:10.1016/j.celrep.2021.109136

Cited by 27 publications

(22 citation statements)

References 71 publications

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“…A recent study describing CRTC3-null mice 43 and CRTC3 function in melanocyte differentiation and melanoma oncogenesis reported coat color phenotypes similar to those observed in our study. However, in contrast to our study, downregulation of MITF, tyrosinase, and DCT expression in CRTC3-null mice was not observed and instead OCA2 was proposed as a CRTC3 target.…”

Section: Discussionsupporting

confidence: 90%

CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders

et al. 2021

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Background: Although CREB phosphorylation is known to be essential in UVB/cAMP-stimulated melanogenesis, CREB null mice did not show identifiable pigmentation phenotypes. Here, we show that CREB-regulated transcription co-activator 3 (CRTC3) quantitatively regulates and orchestrates melanogenesis by directly targeting microphthalmia-associated transcription factor (MITF) and regulating the expression of most key melanogenesis-related genes. Methods: We analyzed CRTC3-null, KRT14-SCF transgenic, and their crossover mice. The molecular basis of CRTC3 effects on pigmentation was investigated by histology, melanin/tyrosinase assay, immunoblotting, shRNA, promoter assay, qRT-PCR, and subcellular localization. These analyses were carried out in primary cultured melanocytes, mouse cell lines, normal human cells, co-cultures, and ex vivo human skin. CRTC/CREB activity screening was performed to identify candidate agents for the regulation of melanogenesis. Results: The coat and skin color of CRTC3-null mice was paler due to a reduction in melanin deposition. Melanogenesis-related genes were reduced in CRTC3-deficient cultured melanocytes and tail skin of CRTC3-null mice. Notably, basal levels of MITF present in CRTC3-null mice were sufficient for melanocytic differentiation/survival. Thus CRTC3-null mice showed a comparable number of epidermal melanocytes compared to control mice. Stem cell factor (SCF) introduction by crossing with KRT14-SCF mice increased epidermal melanocytes and melanin deposition in control and CRTC3-null mice, but the skin color remained still light on the CRTC3-null background. Furthermore, we identified the therapeutic potential of altiratinib to inhibit melanogenesis in human melanocytes and human skin effectively and safely. Conclusion: CRTC3 appears to be a key sensor for melanogenesis and can be used as a reversible and tunable tool for selectively regulating melanogenesis without affecting melanocyte integrity. Thus, CRTC3 can also serve as a screening tool for the discovery of ideal melanogenesis-modulating small molecules.

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Section: Discussionsupporting

confidence: 90%

CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders

et al. 2021

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“…The catalytic Cα subunit renders BRAF V600E melanoma cells resistant to MAPK inhibitors [126]. The CRTC3 protein, a co-activator of CREB that is phosphorylated and activated by PKA and ERK [144], lies at the interface between signaling through the cAMP and MAPK pathways. A knockout mouse model for Crct3 showed graying of the coat due to defects in melanocyte maturation [144].…”

Section: Signaling Via Campmentioning

confidence: 99%

Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma

Raymond

Aktary

Larue

et al. 2022

Cancers

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G-protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G-proteins, which induce cellular signaling through various pathways. Such signaling modulates numerous essential cellular processes that occur during melanomagenesis, including proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden melanoma treatment options in the future.

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“…The catalytic Cα subunit renders BRAF V600E melanoma cells resistant to MAPK inhibitors [120]. The CRTC3 protein, a co-activator of CREB that is phosphorylated and activated by PKA and ERK [138], lies at the interface between signaling through the cAMP and MAPK pathways. A knockout mouse model for Crct3 showed graying of the coat due to defects in melanocyte maturation [138].…”

Section: A Signaling Via Campmentioning

confidence: 99%

“…The CRTC3 protein, a co-activator of CREB that is phosphorylated and activated by PKA and ERK [138], lies at the interface between signaling through the cAMP and MAPK pathways. A knockout mouse model for Crct3 showed graying of the coat due to defects in melanocyte maturation [138]. Mutations in CRCT3 have been identified in 23% of human melanomas, most leading to an increase in its expression and activity and reduced patient survival [138].…”

Section: A Signaling Via Campmentioning

confidence: 99%

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Targeting GPCRs & their Signaling as a Therapeutic Option in Melanoma

Raymond¹,

Aktary²,

Larue³

et al. 2022

Preprint

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G protein-coupled receptors (GPCRs) serve prominent roles in melanocyte lineage physiology, with an impact at all stages of development, as well as on mature melanocyte functions. GPCR ligands are present in the skin and regulate melanocyte homeostasis, including pigmentation. The role of GPCRs in the regulation of pigmentation and, consequently, protection against external aggression, such as ultraviolet radiation, has long been established. However, evidence of new functions of GPCRs directly in melanomagenesis has been highlighted in recent years. GPCRs are coupled, through their intracellular domains, to heterotrimeric G proteins, which induce cellular signaling through various pathways. Such signaling modulates essential cellular processes of melanomagenesis, such as proliferation and migration. GPCR-associated signaling in melanoma can be activated by the binding of paracrine factors to their receptors or directly by activating mutations. In this review, we present melanoma-associated alterations of GPCRs and their downstream signaling and discuss the various preclinical models used to evaluate new therapeutic approaches against GPCR activity in melanoma. Recent striking advances in our understanding of the structure, function, and regulation of GPCRs will undoubtedly broaden treatment options in melanoma in the future.

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Transcriptional co-activator regulates melanocyte differentiation and oncogenesis by integrating cAMP and MAPK/ERK pathways

Abstract: Highlights d CRTC3 knockout mice have decreased fur pigmentation d Melanosome maturation is defective in CRTC3 knockout melanocytes d CREB and CRTC3 promote OCA2 expression in melanocytes d Increased CRTC3 expression/activity in melanomas correlates with reduced survival

Cited by 27 publications

References 71 publications

CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders

CRTC3, a sensor and key regulator for melanogenesis, as a tunable therapeutic target for pigmentary disorders

Targeting GPCRs and Their Signaling as a Therapeutic Option in Melanoma

Targeting GPCRs & their Signaling as a Therapeutic Option in Melanoma

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