BRAF/MAPK and GSK3b signalling signaling converge to control MITF nuclear export

ABSTRACT: The close integration of the MAPK, PI3K and WNT signaling pathways underpins much of development and is deregulated in cancer. In principle, combinatorial post-translational 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. Yet how the activity of this key transcription factor is controlled remains poorly understood. Here we show that GSK3b, downstream from both the PI3K and Wnt pathways, and BRAF/MAPK signaling converge to control MITF nuclear export. Phosphorylation of the melanocyte MITF-M isoform in response to BRAF/MAPK signaling primes for phosphorylation by GSK3b, 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

INSTRUMENT(S): Q Exactive

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Epithelial Cell

DISEASE(S): Melanomatosis

SUBMITTER: Georgina Berridge  

LAB HEAD: Roman Fischer

PROVIDER: PXD010665 | Pride | 2022-02-28

REPOSITORIES: Pride