Comparative genetic screens in human cells reveal new regulatory mechanisms in WNT signaling

作者：Lebensohn Andres M; Dubey Ramin; Neitzel Leif R; Tacchelly Benites Ofelia; Yang Eungi; Marceau Caleb D; Davis Eric M; Patel Bhaven B; Bahrami Nejad Zahra; Travaglini Kyle J; Ahmed Yashi; Lee Ethan; Carette Jan E^*; Rohatgi Rajat^*

来源：eLife, 2016, 5: e21459.

DOI：10.7554/eLife.21459

The comprehensive understanding of cellular signaling pathways remains a challenge due to multiple layers of regulation that may become evident only when the pathway is probed at different levels or critical nodes are eliminated. To discover regulatory mechanisms in canonical WNT signaling, we conducted a systematic forward genetic analysis through reporter-based screens in haploid human cells. Comparison of screens for negative, attenuating and positive regulators of WNT signaling, mediators of R-spondin-dependent signaling and suppressors of constitutive signaling induced by loss of the tumor suppressor adenomatous polyposis coli or casein kinase 1 alpha uncovered new regulatory features at most levels of the pathway. These include a requirement for the transcription factor AP-4, a role for the DAX domain of AXIN2 in controlling beta-catenin transcriptional activity, a contribution of glycophosphatidylinositol anchor biosynthesis and glypicans to R-spondin-potentiated WNT signaling, and two different mechanisms that regulate signaling when distinct components of the beta-catenin destruction complex are lost. The conceptual and methodological framework we describe should enable the comprehensive understanding of other signaling systems.

• 出版日期2016-12-20