According to the study, WNT signaling pathways play important roles in cell growth, development and cancer. The classical or canonical WNT pathway and its atypical; non-canonical counterpart share a protein called DVL2 that “transduces” or converts one kind of signal to another. shown that two other proteins; USP9X and WWP1, act on DVL2 to regulate both WNT signaling pathways.
But whereas WWP1 suppresses DVL2 by tagging it with a protein called ubiquitin; that marks it for degradation, USP9X promotes WNT activation by releasing DVL2 from ubiquitin; and rescuing it from degradation. The WNT signaling network is comprising of multiple receptors; that relay various input signals via distinct transduction pathways to execute multiple complex and context-specific output processes.
The canonical WNT β-catenin signaling pathway is involved in regulating many cellular processes such as cell fate determination during embryonic development, cell proliferation, and adult tissue homeostasis. Integrity of the WNT signaling network relying on proper specification between canonical and noncanonical pathways; which presents a regulatory challenge given that several signal transducing elements are sharing between pathways.
WNT signaling pathways
Here, we report that USP9X, a deubiquitylase, and WWP1, an E3 ubiquitin ligase, regulate a ubiquitin rheostat on DVL2, a WNT signaling protein. Study findings indicate that USP9X-mediating deubiquitylation of DVL2 is requiring for canonical WNT activation; while increased DVL2 ubiquitylation is associating with localization to actin-rich projections and activation of the planar cell polarity (PCP) pathway.
The propose that a WWP1-USP9X axis regulating a ubiquitin rheostat on DVL2; that specifies its participation in either canonical WNT or WNT-PCP pathways. These findings have important implications for therapeutic targeting of USP9X in human cancer. There are also several noncanonical WNT signaling pathways including the WNT-planar cell polarity (WNT-PCP) pathway, which controls cell migration and tissue polarity.
Small molecule inhibitor
Dysregulation of the WNT-PCP pathway has been linking to cancer invasion and metastasis. This increase in cell motility was complementing in cells; transiently transfecting with GFP-USP9X . Consistent with this observation; we also found that treatment of MDA-MB-231 cells with WP1130 a small molecule inhibitor of USP9X; also resulting in a significant increase in the speed of cell motility.
Importantly, the increased cell speed observed in usp9x knockout cells was dependent on VANGL1; indicating the increasing motility phenotype requires an intact WNT-PCP pathway. This result implicates DVL2 as a mediator of the cell motility phenotype observing for usp9xknockout cells; but it does not inform as to the role of ubiquitylation; since both wild-type and lysine-deficient DVL2 fully suppress the usp9x knockout phenotype.