APC is K63 polyubiquitinated in the absence of WNT signal and this modification correlates with AXIN binding. Depletion of AXIN or beta-catenin by RNAi abrogates APC polyubiquitination, as does inhibition of GSK3 kinase activity, suggesting that polyubiquitination depends on the assembly of a functional destruction complex. WNT3A pathway activation promotes a loss of APC-AXIN interaction concurrent with loss of APC polyubiquitination (Tran and Polakis, 2012).
Polyubiquitination of APC is lost in a number of human cancer cell lines that express truncated forms of APC and which show hyperactivation of the WNT signaling pathway (Tran and Polakis, 2012). The loss of APC polyubiquitination in these lines may reflect the fact that the APC mutants are compromised in their ability to interact with AXIN due to truncation/loss of the AXIN-binding SAMP repeats (Spink et al, 2000); alternately, the truncations may remove as-yet unidentified polyubiquitination sites. APC polyubiquitination is also lost in cancer lines carrying mutations in AXIN that disrupt interaction with GSK3 as well as in cell lines with phosphodegron mutations of beta-catenin (Tran and Polakis, 2012).