IQGAP1 binds to YAP and modulates its transcriptional activity

Authors

• S Sayedyahossein
• Z Li
• AC Hedman
• CJ Morgan
• DB Sacks

Abstract

The Hippo pathway compromises a large group of proteins that integrate with key signaling cascades to regulate regeneration and stem cell biology. Yes-associated protein (YAP) is a major transcriptional co-activator of the Hippo pathway. Hyperactivation of YAP is widespread in cancers. Through association with transcription factors, such as TEA domain family members (TEAD), YAP regulates transcription to drive gene expression. IQGAP1 is a scaffold protein that interacts with more than 100 binding partners, including transcription factors, such as β-catenin, to integrate signaling pathways involved in regulation of cell polarity, cell-cell adhesion, migration, invasion and tumorigenesis. Since IQGAP1 is a component of receptor signaling cascades, we postulated that IQGAP1 may participate in Hippo signaling. To test this hypothesis we used different strategies, including binding studies with pure proteins, cultured cells with CRISPR/Cas9 knockdown, cells from IQGAP1-null mice and transcription assays. In this study, we demonstrate that endogenous IQGAP1 and YAP co-immunoprecipitated from cells. In vitro analysis with pure proteins revealed direct binding of IQGAP1 to YAP. Analysis using multiple fragments of each protein showed that the interaction occurs via the IQ domain of IQGAP1 and the TEAD-binding domain of YAP. The interaction between IQGAP1 and YAP has functional effects. Knockout of endogenous IQGAP1 significantly increased the formation of nuclear TEAD/YAP complexes. Furthermore, induction of TEAD-mediated transcription by YAP was 3.8 +/- 0.7-fold greater in cells lacking IQGAP1 than control cells. These data indicate that IQGAP1 binds to YAP and modulates its co-transcriptional function, suggesting that IQGAP1 may participate in Hippo signaling.

Scientific Focus Area: Molecular Biology and Biochemistry

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