Alternative splicing of the Wnt trafficking protein, Wntless and its effects on protein-protein interactions.

BACKGROUND:Wntless (Wls) is a protein that regulates secretion of Wnt signaling molecules from Wnt-producing cells. Wnt signaling is known to be critical for several developmental and homeostatic processes. However, Wnt-independent functions of Wls are now being elucidated. Primates express an alternative splice variant of Wls (here termed WlsX). WlsX contains an alternatively spliced COOH-terminus, and does not appear to be able to sustain significant levels of WNT secretion because of its inability to undergo retrograde trafficking to the endoplasmic reticulum. The functional significance for this alternatively spliced form of Wls has not yet been elucidated. We previously identified a cohort of Wls interacting proteins using a combination of yeast 2-hybrid and candidate gene approaches. RESULTS:In the present study, we analyzed the interaction of WlsX with previously identified Wls interactors, and additionally screened for novel protein interactors of WlsX utilizing a membrane yeast two hybrid screen. Three novel Wls interactors, Glycoprotein M6A (GPM6A), Alkylglycerol Monooxygenase (AGMO), and ORAI1 were identified. Each of these novel WlsX interactors, as well as all other Wls interacting proteins identified previously, with the exception of the mu-opioid receptor, were found to interact with both Wls and WlsX splice forms. We show that WlsX can form homodimers, but that WlsX may not interact with Wls. CONCLUSIONS:WlsX has the ability to form homodimers and to interact with most known Wls interacting proteins. Taken together, our results suggest that Wls and WlsX may have overlapping, but distinct functions, including sensitivity to opioid drugs. While studies have focused on the ability of Wls interacting proteins to affect Wnt secretion, future efforts will explore the reciprocal regulation of these proteins by Wls, possibly via Wnt-independent mechanisms.

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