PROJECT SUMMARY/ABSTRACT Melanoma is the deadliest form of skin cancer and is one of the most difficult cancer to treat. Therefore, the underlying mechanism of melanomagenesis and melanoma development demands intensive study. Recent findings identified that palmitoylation of melanocortin-1 receptor (MC1R), primarily mediated by the protein-acyl transferase (PAT) ZDHHC13, is essential for activating MC1R signaling and prevent melanomagenesis. Preliminary studies also revealed that APT2 is the major depalmitoylating enzyme of MC1R and is harmful for metastatic melanoma patients. In this proposed study, I aim to elucidate the in-depth molecular mechanism by which ZDHHC13/APT2-regulated palmitoylation repress melanoma development and progression, and test the hypothesis that ZDHHC13/APT2-regulated palmitoylation is essential for melanomagenesis and melanoma metastasis in vivo. During the mentored K99 phase, I will elucidate the underlying regulatory mechanism of ZDHHC13 in melanocytes by using new developed ZDHHC13 transgenic mice. I will also characterize the effects of depalmitoylation inhibition in melanomagenesis by targeting APT2. During the independent R00 phase, I plan to determine the role of ZDHHC13/APT2-regulated palmitoylation in melanoma metastasis in vivo and identify whether inhibition of depalmitoylation improves survival by suppressing metastasis. Furthermore, I will need additional trainings during the award period in melanoma mouse model, targeted therapy, as well as professional skills which will contribute to my long term career goal. In summary, successful completion of my proposed studies will bring novel insights into the roles and molecular mechanisms of ZDHHC13/APT2-regulated palmitoylation in melanoma development and progression, which can be translated into new intervention and treatment strategies. Receipt of this award will allow me to expand my research plan and serve as a platform for me to receive additional trainings, thus prepare myself becoming an independent principal investigator in the field of melanoma research.