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 pro-metastatic 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.
Highlights
The Wnt5a signaling pathway plays a critical role in multiple biological processes as it regulates cell polarity and polarized cell movement during embryonic development
We hypothesized a mechanism for increased depalmitoylation could be a result of regulatory post-translational modifications of acyl protein thioesterase 1 (APT1) that increases APT1 activity
To investigate if APT1 is post-translationally modified in response to Wnt5a stimulation, we used mass spectrometry to identify Wnt5a dependent post-translational modifications (PTMs) of APT1
Summary
The Wnt5a signaling pathway plays a critical role in multiple biological processes as it regulates cell polarity and polarized cell movement during embryonic development. The elevated expression of Wnt5a in human melanoma samples and subsequent in vitro studies have suggested a role for Wnt5a in melanoma metastasis (Bittner et al, 2000; Carr et al, 2003; Da Forno et al, 2008). Wnt5a expression is positively correlated with poor outcome, with high Wnt5a expression being associated with decreased patient survival (Da Forno et al, 2008). With this information, it has been suggested that Wnt5a expression be used as a prognostic clinical risk factor (Da Forno et al, 2008). Elucidation of the signaling events downstream of Wnt5a that promote polarized cell movement and metastatic behavior have the potential to enhance our understanding of the contribution of Wnt5a to melanoma metastasis
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