MITF potentiates Wnt Signaling

PLOPER, D

Malibu, California

Encuentro; UCLA Department of Biological Chemistry Retreat; 2013

Department of Biological Chemistry, UCLA

Wnt signaling stabilizes many proteins. In a bioinformatics screen, MITF/TFEB family of bHLH transcription factors have the most conserved GSK3 phosphorylation sites. TFEB is the master regulator of lysosome biogenesis, while MITF is the master gene regulator of melanocytes. MITF is a lineage survival oncogene, amplified in 15% of melanomas, and a mutation that stabilizes the protein gives familial melanoma. Here, we report that Wnt signaling stabilizes MITF protein. Furthermore, MITF triggers lysosomal/MVB biogenesis, similar to TFEB. This increase in vesicular organelles results in potentiation of Wnt signaling. This positive feed-forward signaling loop could have implications in melanoma.1) Wnt signaling requires Multivesicular Bodies (MVBs). 2) Wnt, through GSK3 inhibition, may regulate MITF and TFEB. 3) MITF is the melanocyte Master Gene Regulator. 4) Wnt signaling stabilizes MITF. 5) MITF expands the endo/lysosomal compartment. 6) MITF potentiates Wnt signaling. 7) MITF increases sequestration of destruction complexes in MVBs during Wnt signaling. 8) Conclusions:1) Wnt stabilizes MITF. 2) MITF expands the endo/lysosomal compartment. 3) MITF potentiates Wnt signaling by increasing the sequestration of destruction complexes in MVBs.