期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 37, 页码 E8668-E8677出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1810498115
关键词
MITF; melanoma; MAPK; nuclear export; GSK3
资金
- Agency for Science, Technology and Research Singapore
- Cancer Research UK (CRUK) Grant, through a CRUK Oxford Centre Prize DPhil Studentship [C38302/A12981]
- China Scholarship Council
- Wellcome Trust Career Development Fellowship [095751/Z/11/Z]
- Structural Genomics Consortium
- Arthritis Research UK [MP/19200]
- Rosetrees Trust [M456]
- Research Fund of Iceland
- Ludwig Institute for Cancer Research
- Kennedy Trust Fund
- Medical Research Council Human Genetics Unit Programme [MC_PC_U127585840]
- European Research Council [ZF-MEL-CHEMBIO-g48489]
- L'Oreal-Melanoma Research Alliance Grant [401181]
- NIH [NIH 98571, NIH 80728]
- Rosetrees Trust [M456] Funding Source: researchfish
- Versus Arthritis [19200] Funding Source: researchfish
- MRC [MR/N010051/1, MC_UU_00007/9, MC_PC_U127585840, MC_U127585840] Funding Source: UKRI
The close integration of the MAPK, PI3K, and WNT signaling pathways underpins much of development and is deregulated in cancer. In principle, combinatorial posttranslational modification of key lineage specific transcription factors would be an effective means to integrate critical signaling events. Understanding how this might be achieved is central to deciphering the impact of microenvironmental cues in development and disease. The microphthalmia-associated transcription factor MITF plays a crucial role in the development of melanocytes, the retinal pigment epithelium, osteoclasts, and mast cells and acts as a lineage survival oncogene in melanoma. MITF coordinates survival, differentiation, cell-cycle progression, cell migration, metabolism, and lysosome biogenesis. However, how the activity of this key transcription factor is controlled remains poorly understood. Here, we show that GSK3, downstream from both the PI3K and Wnt pathways, and BRAF/MAPK signaling converges to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3, a kinase inhibited by both PI3K and Wnt signaling. Dual phosphorylation, but not monophosphorylation, then promotes MITF nuclear export by activating a previously unrecognized hydrophobic export signal. Nonmelanocyte MITF isoforms exhibit poor regulation by MAPK signaling, but instead their export is controlled by mTOR. We uncover here an unanticipated mode of MITF regulation that integrates the output of key developmental and cancer-associated signaling pathways to gate MITF flux through the import export cycle. The results have significant implications for our understanding of melanoma progression and stem cell renewal.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据