Proper folding and endoplasmic reticulum to Golgi transport of tyrosinase are induced by its substrates, DOPA and tyrosine

Tyrosinase is essential for pigmentation and is a source of tumor-derived a ntigenic peptides and cellular immune response. Wild type tyrosinase in mel anoma cells and certain albino mutants in untransformed melanocytes are tar geted to proteolytic degradation by the 26 S proteasome due to retention of the misfolded protein in the endoplasmic reticulum and its subsequent retr anslocation to the cytosol. Here, we demonstrate that the substrates DOPA a nd tyrosine induced in melanoma cells a transition of misfolded wild type t yrosinase to the native form that is resistant to proteolysis, competent to exit the endoplasmic reticulum, and able to produce melanin. Because the e nzymatic activity of tyrosinase is induced by DOPA, we propose that proper folding of the wild type protein, just like mutant forms, is tightly linked to its catalytic state. Loss of pigmentation, therefore, in tyrosinase-pos itive melanoma cells is a consequence of tumor-induced metabolic changes th at suppress tyrosinase activity and DOPA production within these cells.