MITF potentiates Wnt signaling

PLOPER, D; DE ROBERTIS, EDWARD M.

Chevy Chase, Maryland

Encuentro; Howard Hughes Medical Institute (HHMI) Science Meeting; 2012

Howard Hughes Medical Institute (HHMI)

Wnt signaling plays an pivotal role in development and disease by regulating the transcription of target genes and stabilizing many proteins phosphorylated by GSK3. We found that the MiT family of transcription factors, which includes the melanoma oncogene MITF and the lysosomal master regulator TFEB, had the highest phylogenetic conservation of putative GSK3 phosphorylation sites. We found that MITF levels correlate with many lysosomal genes in melanoma. MITF over-expression caused an increase in vesicules marked by the expression of late endosomal proteins Rab7, LAMP1, and CD63. These late endolysosomes were less active in proteolysis. However, they were able to accumulate Axin1, phospho-LRP6, phospho-beta-catenin, and GSK3 when incubated with Wnt. This accumulation of Wnt components enhanced Wnt signaling by augmenting the number of MVBs where the signalosome/destruction is sequestered. MITF protein was also stabilized by Wnt signaling, mediated by novel GSK3 phosphorylations. This positive-feedback loop may be important in proliferative stages of melanoma development. These results underscore the importance of misregulated endolysosomal biogenesis not only for Wnt signaling, but also in diseases such as cancer.