The cyclic AMP pathway promotes melanocyte differentiation in part by triggering gene expression changes mediated by CREB and its coactivators (CRTC1-3). Differentiation is dysregulated in melanomas, although the contributions of different cAMP effectors in this setting is unclear. We report a selective differentiation impairment in CRTC3 KO melanocytes and melanoma cells, due to downregulation of OCA2 and block of melanosome maturation. CRTC3 stimulated OCA2 expression via binding to CREB on a conserved enhancer, a regulatory site for pigmentation and melanoma risk in humans. Response to cellular signaling differed between CRTC3 and its family members; CRTC3 was uniquely activated by ERK1/2-mediated phosphorylation at Ser391 and by low levels of cAMP. Phosphorylation at Ser391 was constitutively elevated in human melanoma cells with hyperactivated ERK1/2 signaling; knockout of CRTC3 in this setting impaired anchorage-independent growth, migration and invasiveness while CRTC3 overexpression supported cell survival in response to MAPK inhibition by vemurafenib. Human melanomas expressing gain of function mutations in CRTC3 were associated with poorer clinical outcome. Our results suggest that CRTC3 inhibition may provide benefit in the treatment of hyperpigmentation and melanoma, and potentially other disorders with deregulated cAMP/MAPK crosstalk.

中文翻译：

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转录共激活因子通过整合cAMP和MAPK / ERK途径调节黑素细胞的分化和肿瘤发生

环状AMP途径部分通过触发CREB及其共激活因子（CRTC1-3）介导的基因表达变化来促进黑素细胞分化。黑色素瘤的分化失调，尽管尚不清楚在这种情况下不同cAMP效应子的作用。我们报告CRTC3 KO黑色素细胞和黑色素瘤细胞的选择性分化障碍，由于下调OCA2和黑素体成熟的阻止。CRTC3通过与保守增强子上的CREB结合来刺激OCA2表达，CREB3是人体内色素沉着和黑色素瘤风险的调控位点。CRTC3及其家族成员对细胞信号的反应有所不同。CRTC3被Ser391处的ERK1 / 2介导的磷酸化和低水平的cAMP唯一激活。在人类黑色素瘤细胞中，ER391 / 2信号过度激活，Ser391的磷酸化水平显着升高。在这种情况下敲除CRTC3会损害锚定非依赖性的生长，迁移和侵袭性，而CRTC3的过表达则支持了维罗非尼对MAPK抑制反应的细胞存活。在CRTC3中表达功能突变的人黑色素瘤与较差的临床预后相关。我们的结果表明，抑制CRTC3可能在色素沉着过多和黑色素瘤以及cAMP / MAPK串扰失控的其他疾病的治疗中提供益处。在CRTC3中表达功能突变的人黑色素瘤与较差的临床预后相关。我们的结果表明，抑制CRTC3可能在色素沉着过多和黑色素瘤以及cAMP / MAPK串扰失控的其他疾病的治疗中提供益处。在CRTC3中表达功能突变的人黑色素瘤与较差的临床预后相关。我们的结果表明，抑制CRTC3可能在色素沉着过多和黑色素瘤以及cAMP / MAPK串扰失控的其他疾病的治疗中提供益处。