@article{f15d7952e6854ed7a642d9c863221c62,
title = "Wnt5a signaling induced phosphorylation increases APT1 activity and promotes melanoma metastatic behavior",
abstract = "Wnt5a has been implicated in melanoma progression and metastasis, although the exact downstream signaling events that contribute to melanoma metastasis are poorly understood. Wnt5a signaling results in acyl protein thioesterase 1 (APT1) mediated depalmitoylation of prometastatic cell adhesion molecules CD44 and MCAM, resulting in increased melanoma invasion. The mechanistic details that underlie Wnt5a-mediated regulation of APT1 activity and cellular function remain unknown. Here, we show Wnt5a signaling regulates APT1 activity through induction of APT1 phosphorylation and we further investigate the functional role of APT1 phosphorylation on its depalmitoylating activity. We found phosphorylation increased APT1 depalmitoylating activity and reduced APT1 dimerization. We further determined APT1 phosphorylation increases melanoma invasion in vitro, and also correlated with increased tumor grade and metastasis. Our results further establish APT1 as an important regulator of melanoma invasion and metastatic behavior. Inhibition of APT1 may represent a novel way to treat Wnt5a driven cancers.",
author = "Sadeghi, {Rochelle Shirin} and Katarzyna Kulej and Kathayat, {Rahul Singh} and Garcia, {Benjamin A.} and Dickinson, {Bryan C.} and Brady, {Donita C.} and Witze, {Eric S.}",
note = "Funding Information: This work was supported by NIH Grants R01CA181633 and AI118891, ACS Grants RSG-15-027-01, IRG –78-002-34. This project is funded, in part, under a grant with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. D.C.B. is funded by the Pew Biomedical Scholars Program #29622. We would like to thank Rachel Ekaireb for initial characterization of the APT1 mutants. We would also like to thank Dr. Todd Ridky, Dr. Christopher Natale, and Dr. Luca Busino for their help and support throughout the research project. National Institute of Allergy and Infectious Diseases AI118891 Benjamin A Garcia National Cancer Institute CA181633 Eric S Witze American Cancer Society RSG-15-027-01 Eric S Witze American Cancer Society IRG –78-002-34 Eric S Witze. Funding Information: This work was supported by NIH Grants R01CA181633 and AI118891, ACS Grants RSG-15-027-01, IRG –78-002-34. This project is funded, in part, under a grant with the Pennsylvania Department of Health. The Department specifically disclaims responsibility for any analyses, interpretations or conclusions. D.C.B. is funded by the Pew Biomedical Scholars Program #29622. We would like to thank Rachel Ekaireb for initial characterization of the APT1 mutants. We would also like to thank Dr. Todd Ridky, Dr. Christopher Natale, and Dr. Luca Busino for their help and support throughout the research project. Publisher Copyright: {\textcopyright} Sadeghi et al.",
year = "2018",
month = apr,
day = "12",
doi = "10.7554/eLife.34362",
language = "English",
volume = "7",
journal = "eLife",
issn = "2050-084X",
}