The Hippo pathway effector proteins YAP and TAZ have both distinct and overlapping functions in the cell

Identifying novel therapeutic targets for the treatment of prostate cancer (PC) remains a key area of research. With the emergence of resistance to androgen receptor (AR)-targeting therapies, other signalling pathways which crosstalk with AR signalling are important. Over recent years, evidence has accumulated for targeting the Hippo signalling pathway. Discovered in Drosophila melanogasta, the Hippo pathway plays a role in the regulation of organ size, proliferation, migration and invasion. In response to a variety of stimuli, including cell–cell contact, nutrients and stress, a kinase cascade is activated, which includes STK4/3 and LATS1/2 to inhibit the effector proteins YAP and its paralogue TAZ. Transcription by their partner transcription factors is inhibited by modulation of YAP/TAZ cellular localisation and protein turnover. Trnascriptional enhanced associate domain (TEAD) transcription factors are their classical transcriptional partner but other transcription factors, including the AR, have been shown to be modulated by YAP/TAZ. In PC, this pathway can be dysregulated by a number of mechanisms, making it attractive for therapeutic intervention. This review looks at each component of the pathway with a focus on findings from the last year and discusses what knowledge can be applied to the field of PC.

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RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway

Science Signaling ◽

10.1126/scisignal.abb4778 ◽

2020 ◽

Vol 13 (653) ◽

pp. eabb4778 ◽

Cited By ~ 1

Author(s):

Thillaivillalan Dhanaraman ◽

Swati Singh ◽

Ryan C. Killoran ◽

Anamika Singh ◽

Xingjian Xu ◽

...

Keyword(s):

Hippo Pathway ◽

Effector Proteins ◽

Domain Family ◽

Ras Gtpases ◽

Downstream Effector ◽

Ras Superfamily ◽

Ras Family ◽

Key Residues ◽

The Hippo Pathway ◽

Apoptotic Induction

Small guanosine triphosphatases (GTPases) of the RAS superfamily signal by directly binding to multiple downstream effector proteins. Effectors are defined by a folded RAS-association (RA) domain that binds exclusively to GTP-loaded (activated) RAS, but the binding specificities of most RA domains toward more than 160 RAS superfamily GTPases have not been characterized. Ten RA domain family (RASSF) proteins comprise the largest group of related effectors and are proposed to couple RAS to the proapoptotic Hippo pathway. Here, we showed that RASSF1-6 formed complexes with the Hippo kinase ortholog MST1, whereas RASSF7-10 formed oligomers with the p53-regulating effectors ASPP1 and ASPP2. Moreover, only RASSF5 bound directly to activated HRAS and KRAS, and RASSFs did not augment apoptotic induction downstream of RAS oncoproteins. Structural modeling revealed that expansion of the RASSF effector family in vertebrates included amino acid substitutions to key residues that direct GTPase-binding specificity. We demonstrated that the tumor suppressor RASSF1A formed complexes with the RAS-related GTPases GEM, REM1, REM2, and the enigmatic RASL12. Furthermore, interactions between RASSFs and RAS GTPases blocked YAP1 nuclear localization. Thus, these simple scaffolds link the activation of diverse RAS family small G proteins to Hippo or p53 regulation.

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RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway

10.1101/2020.02.05.923433 ◽

2020 ◽

Author(s):

Dhanaraman Thillaivillalan ◽

Swati Singh ◽

Ryan C. Killoran ◽

Anamika Singh ◽

Xingjian Xu ◽

...

Keyword(s):

Amino Acid ◽

Nuclear Localization ◽

Hippo Pathway ◽

Effector Proteins ◽

Amino Acid Substitutions ◽

Structural Modelling ◽

Ras Proteins ◽

Domain Family ◽

Ras Gtpases ◽

The Hippo Pathway

AbstractActivated RAS GTPases signal by directly binding effector proteins. Effectors have a folded RAS association (RA) domain that binds exclusively to GTP-loaded RAS, but the specificity of most RA domains for >150 RAS superfamily GTPases is unknown. Ten RAS-association domain family (RASSF) proteins comprise the largest group of effectors, proposed to couple RAS to the pro-apoptotic Hippo pathway. We show that RASSF1-6 complex with Hippo kinase, while RASSF7-10 are a separate family related to p53-regulatory ASPP effectors. Only RASSF5 directly binds activated HRAS and KRAS. Structural modelling reveals that expansion of RASSFs in vertebrates included amino acid substitutions that alter their GTPase binding specificity. We demonstrate that the tumour suppressor RASSF1A complexes with the GTPases GEM, REM1, REM2 and the enigmatic RASL12. Interplay between RASSFs and RAS GTPases can drastically restrict YAP1 nuclear localization. Thus, these simple scaffolds can link activation of diverse RAS proteins to Hippo or p53 regulation.

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TAZ inhibits GR and coordinates hepatic glucose homeostasis in normal physiologic states

10.1101/2020.05.12.091264 ◽

2020 ◽

Author(s):

Simiao Xu ◽

Yangyang Liu ◽

Ruixiang Hu ◽

Min Wang ◽

Oliver Stöhr ◽

...

Keyword(s):

Glucose Homeostasis ◽

Blood Glucose Concentration ◽

Hippo Pathway ◽

Glucose Production ◽

Effector Proteins ◽

Binding Motif ◽

Gene Promoters ◽

Hepatic Glucose ◽

The Hippo Pathway

AbstractThe elucidation of the mechanisms whereby the liver maintains glucose homeostasis is crucial for the understanding of physiologic and pathologic states. Here, we show a novel role of hepatic transcriptional co-activator with PDZ-binding motif (TAZ) in the inhibition of glucocorticoid receptor (GR). TAZ interacts via its WW domain with the ligand-binding domain of GR to limit the binding of GR to gluconeogenic gene promoters. Therefore, liver-specific TAZ knockout mice show increases in glucose production and blood glucose concentration. Conversely, the overexpression of TAZ in mouse liver reduces the binding of GR to gluconeogenic gene promoters and glucose production. Thus, our findings demonstrate distinct roles of the hippo pathway effector proteins yes-associated protein 1 (YAP) and TAZ in liver physiology: while deletion of hepatic YAP has little effect on glucose homeostasis, hepatic TAZ protein expression decreases upon fasting and coordinates gluconeogenesis in response to physiologic fasting and feeding.

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