Wnt/Beta-catenin signaling and ARTD family members (WP5529)

Positive regulation Tankyrase 1 and Tankyrase 2 (PARP5a/b or ARTD5/6) play key roles in regulating telomere length, centrosome maturation, proteasome assembly, and the formation of the mitotic spindle. Interestingly, Tankyrase 1/2 also appear to regulate β-catenin stability, and consequently, active Wnt signaling, as the deletion of both Tankyrase 1 and 2 leads to early embryonic lethality in mice. In this context, inhibiting Tankyrase 1/2 destabilizes β-catenin by promoting Axin stability, which in turn reduces the growth of β-catenin-dependent colorectal cancer cells. GSK3 kinase activity is a critical suppressor of β-catenin stability, and this activity is negatively regulated by mono-ADP-ribosylation mediated by PARP10, which results in elevated β-catenin levels. Moreover, PLK1 promotes β-catenin destabilization and is mono-ADP-ribosylated by PARP10. This modification of PLK1 significantly diminishes its enzymatic activity, suggesting a potential secondary mechanism through which PARP10 may enhance β-catenin stability. PARP1 enhances Wnt target gene expression in both APC-deficient familial and sporadic colorectal cancer (CRC) by acting as a co-factor of TCF-4/β-catenin. In contrast, Ku70 has been shown to bind to TCF-4/β-catenin and inhibit TCF/LEF function. In colon cancer, overexpression of PARP1 is commonly observed, indicating its supportive role in β-catenin transcriptional activity. Negative regulation As of 2021, no evidence has been reported for negative regulation of Wnt signaling by ARTD family members.

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