Melanin, a skin pigment that protects the skin and eyes from the harmful effects of UV, is synthesized in a specialized lysosome-related organelle called the melanosome. Melanosome maturation is precisely controlled by the sequential delivery of enzymes that synthesize melanin to the developing organelle such that melanin synthesis only occurs in the stage III or IV melanosome. Defects in melanosome maturation are linked to skin cancer susceptibility and skin pigment variation, highlighting the intrinsic biologial relevance of this pathway. While extensive studies have identified vesicle transport pathways that deliver proteins to the melanosome, little is known about what directs transport vesicles to fuse with the developing melanosome. Recent work from our group has identified specific lipid signals that direct vesicles to fuse with the melanosome. In this application, we hypothesize that phosphoinositide signaling coordinates melanosome maturation with the transcription of enzymes that produce melanin. The studies proposed will: 1) identify lipid signals that direct transport vesicles to the melanosome;2) identify cellular signals that direct transport vesicles t fuse with autophagosomes or melanosomes;3) determine how cells coordinate melanosome maturation with the transcription of enzymes that produce melanin and examine the relevance of this pathway in tuberous sclerosis. Completion of the proposed studies will not only enhance our fundamental understanding of how intracellular vesicle transport is coordinated and compartmentalized, but will also lead to the design of pharmacologic agents to stimulate melanosome maturation in skin cancer susceptible patients, reducing the disease burden of the most common type of cancer in the United States.
Both lightly pigmented individuals and those with hypopigmentary disorders (Hermansky-Pudlak syndrome, albinism) accumulate immature melanosomes in their skin, which predisposes them to develop non- melanoma skin cancer. In this proposal, we hypothesize that a novel PI lipid signaling pathway controls the maturation of the early stage melanosome and contributes to both intrinsic skin pigment variation as well as pigment variation observed in human disease (tuberous sclerosis, Hermansky-Pudlak syndrome, albinism). Completion of the proposed studies will not only enhance our fundamental understanding of the pathways that regulate melanosome maturation but also lead to the design of pharmacologic agents to stimulate melanosome maturation in skin cancer susceptible patients, reducing the disease burden of the most common type of cancer in the United States.
|Chen, Chi-Fen; Ruiz-Vega, Rolando; Vasudeva, Priya et al. (2017) ATR Mutations Promote the Growth of Melanoma Tumors by Modulating the Immune Microenvironment. Cell Rep 18:2331-2342|
|Paterson, Elyse K; Fielder, Thomas J; MacGregor, Grant R et al. (2015) Tyrosinase Depletion Prevents the Maturation of Melanosomes in the Mouse Hair Follicle. PLoS One 10:e0143702|