Canonical Wnt signaling plays an important role in development and disease, 
regulating transcription of target genes and stabilizing many proteins 
phosphorylated by glycogen synthase kinase 3 (GSK3). We observed that the MiT 
family of transcription factors, which includes the melanoma oncogene MITF 
(micropthalmia-associated transcription factor) and the lysosomal master 
regulator TFEB, had the highest phylogenetic conservation of three consecutive 
putative GSK3 phosphorylation sites in animal proteomes. This finding prompted 
us to examine the relationship between MITF, endolysosomal biogenesis, and Wnt 
signaling. Here we report that MITF expression levels correlated with the 
expression of a large subset of lysosomal genes in melanoma cell lines. MITF 
expression in the tetracycline-inducible C32 melanoma model caused a marked 
increase in vesicular structures, and increased expression of late endosomal 
proteins, such as Rab7, LAMP1, and CD63. These late endosomes were not 
functional lysosomes as they were less active in proteolysis, yet were able to 
concentrate Axin1, phospho-LRP6, phospho-β-catenin, and GSK3 in the presence of 
Wnt ligands. This relocalization significantly enhanced Wnt signaling by 
increasing the number of multivesicular bodies into which the Wnt 
signalosome/destruction complex becomes localized upon Wnt signaling. We also 
show that the MITF protein was stabilized by Wnt signaling, through the novel 
C-terminal GSK3 phosphorylations identified here. MITF stabilization caused an 
increase in multivesicular body biosynthesis, which in turn increased Wnt 
signaling, generating a positive-feedback loop that may function during the 
proliferative stages of melanoma. The results underscore the importance of 
misregulated endolysosomal biogenesis in Wnt signaling and cancer.