August 27, 2019

A “rheostat” for cancer signals

Jason MacGurn and colleagues have characterized a “rheostat” that sets WNT pathway signaling in breast cancer cells.

by Sanjay Mishra

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.

Now Jason MacGurn, PhD, and colleagues have shown that two other proteins, USP9X and WWP1, act on DVL2 to regulate both WNT signaling pathways.

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.

These antagonistic interactions establish a ubiquitylation “rheostat” on DVL2 that is a critical regulator of WNT pathway specification in human breast cancer cells, and which directs its participation in either WNT pathway, the researchers reported in the journal Cell Reports.

These findings have important implications for therapeutic targeting of WNT pathways in human cancer.

This research was supported by the National Institutes of Health (grants GM101077 and CA095103).