IQGAP1 Is a Scaffold of the Core Proteins of the Hippo Pathway and Negatively Regulates the Pro-Apoptotic Signal Mediated by This Pathway

Abstract

The Hippo pathway regulates a complex signalling network which mediates several biological functions including cell proliferation, organ size and apoptosis. Several scaffold proteins regulate the crosstalk of the members of the pathway with other signalling pathways and play an important role in the diverse output controlled by this pathway. In this study we have identified the scaffold protein IQGAP1 as a novel interactor of the core kinases of the Hippo pathway, MST2 and LATS1. Our results indicate that IQGAP1 scaffolds MST2 and LATS1 supresses their kinase activity and YAP1-dependent transcription. Additionally, we show that IQGAP1 is a negative regulator of the non-canonical pro-apoptotic pathway and may enable the crosstalk between this pathway and the ERK and AKT signalling modules. Our data also show that bile acids regulate the IQGAP1-MST2-LATS1 signalling module in hepatocellular carcinoma cells, which could be necessary for the inhibition of MST2-dependent apoptosis and hepatocyte transformation.

Role of IQGAP1 in Carcinogenesis

“…IQGAP1 interacts with key components of the Hippo pathway, MST2 and LATS1, through its IQ domain and inhibits their activities [53]. The IQ domain of IQGAP1 also binds directly to the TEAD-binding domain of YAP1, a key effector of the Hippo pathway, and therefore competes with TEAD for YAP1 binding [53,54]. IQGAP1 thereby prevents YAP1-TEAD transcription [53,54].…”

“…The IQ domain of IQGAP1 also binds directly to the TEAD-binding domain of YAP1, a key effector of the Hippo pathway, and therefore competes with TEAD for YAP1 binding [53,54]. IQGAP1 thereby prevents YAP1-TEAD transcription [53,54]. Yet, YAP-TEAD interaction increases when IQGAP1 is overexpressed or knocked out [53,54].…”

“…IQGAP1 thereby prevents YAP1-TEAD transcription [53,54]. Yet, YAP-TEAD interaction increases when IQGAP1 is overexpressed or knocked out [53,54]. Overexpression of IQGAP1 also interrupts the YAP1-p73 complex to prevent YAP1-associated pro-apoptotic signaling [53].…”

“…Yet, YAP-TEAD interaction increases when IQGAP1 is overexpressed or knocked out [53,54]. Overexpression of IQGAP1 also interrupts the YAP1-p73 complex to prevent YAP1-associated pro-apoptotic signaling [53]. It is not clear whether IQGAP1 promotes the nuclear localization of YAP1.…”

“…The Hippo pathway controls the organ size and regeneration in the liver [137]. Bile acid is a common factor in liver cancer and upregulates the Hippo pathway both in vitro and in vivo in an IQGAP1-dependent manner [53,138]. In an animal model, bile acid treatment induces IQGAP1 expression [138], which reduces YAP phosphorylation and therefore activates YAP [53,138].…”