scholarly journals RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway

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.

scholarly journals RASSF effectors couple diverse RAS subfamily GTPases to the Hippo pathway

2020 ◽  
Vol 13 (653) ◽  
pp. eabb4778 ◽  
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.

scholarly journals Targeting the Hippo Pathway in Prostate Cancer: What’s New?

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 611
Author(s):  
Kelly Coffey
Keyword(s):  
Prostate Cancer ◽  
Transcription Factors ◽  
Hippo Pathway ◽  
Effector Proteins ◽  
Migration And Invasion ◽  
Cell Contact ◽  
Cellular Localisation ◽  
Kinase Cascade ◽  
The Hippo Pathway ◽  
Emergence Of Resistance

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.

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

2018 ◽  
Vol 293 (28) ◽  
pp. 11230-11240 ◽  
Author(s):  
Steven W. Plouffe ◽  
Kimberly C. Lin ◽  
Jerrell L. Moore ◽  
Frederick E. Tan ◽  
Shenghong Ma ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Effector Proteins ◽  
The Hippo Pathway

scholarly journals Spontaneous recovery from sunitinib-induced disruption of sarcomere in human iPSC-cardiomyocytes and possible involvement of the Hippo pathway

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Toshikatsu Matsui ◽  
Tadahiro Shinozawa
Keyword(s):  
Nuclear Localization ◽  
Spontaneous Recovery ◽  
Hippo Pathway ◽  
Clinical Settings ◽  
Hippo Signaling ◽  
Cardiac Events ◽  
Drug Induced ◽  
Adverse Cardiac Events ◽  
The Hippo Pathway

Abstract Background Sunitinib is known to cause cardiotoxicity in clinical settings. However, among sunitinib-treated patients experiencing adverse cardiac events, decreased cardiac function was reportedly reversible in > 50% of the patients. We previously showed that anti-cancer drugs such as sunitinib cause marked sarcomere disruption in human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), and the extent of sarcomere disruption can be used to predict drug-induced cardiotoxicity in humans. The aim of this study is to investigate whether the reversibility of sunitinib-induced cardiac events in clinical settings can be mimicked in vitro, and to examine the molecular mechanism responsible for sunitinib-induced cardiotoxicity focusing on the Hippo pathway. Methods iPSC-CMs were stimulated with sunitinib for 72 h and the morphology of sarcomere structures were analyzed by high-content analysis before and after sunitinib washout. To examine the involvement of the Hippo pathway in the sunitinib-induced sarcomere disruption, the extent of nuclear localization of YAP1 (yes-associated protein 1, a Hippo signaling target) was determined. iPSC-CMs were also stimulated with sunitinib and a small molecule inhibitor of the Hippo pathway, XMU-MP-1 and sarcomere structures were analyzed. Results We observed a spontaneous recovery in cardiac sarcomeres in iPSC-CMs that were significantly disrupted by sunitinib treatment after a 72 h or 144 h washout of sunitinib. The extent of nuclear localization of YAP1 was significantly reduced after sunitinib stimulation and tended to return to normal levels after drug washout. Simultaneous stimulation of iPSC-CM with sunitinib and XMU-MP-1 suppressed the sunitinib-induced disruption of sarcomeres. Conclusions These results indicate that iPSC-CMs have the ability to recover from sunitinib-induced sarcomere disruption, and the Hippo pathway plays a role in the process of sunitinib-induced disruption of sarcomere and its recovery. Inhibition of the Hippo pathway may help to develop a co-medication strategy for mitigating the risk of sunitinib-induced adverse cardiac events.

scholarly journals Yes-associated protein 1 is required for proliferation and function of bovine granulosa cells in vitro†

2019 ◽  
Vol 101 (5) ◽  
pp. 1001-1017 ◽  
Author(s):  
Michele R Plewes ◽  
Xiaoying Hou ◽  
Pan Zhang ◽  
Aixin Liang ◽  
Guohua Hua ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Nuclear Localization ◽  
Granulosa Cells ◽  
Hippo Pathway ◽  
Critical Role ◽  
Small Cells ◽  
Hippo Signaling ◽  
Hippo Signaling Pathway ◽  
The Hippo Pathway

Abstract Yes-associated protein 1 (YAP1) is a major component of the Hippo signaling pathway. Although the exact extracellular signals that control the Hippo pathway are currently unknown, increasing evidence supports a critical role for the Hippo pathway in embryonic development, regulation of organ size, and carcinogenesis. Granulosa cells (GCs) within the ovarian follicle proliferate and produce steroids and growth factors, which facilitate the growth of follicle and maturation of the oocyte. We hypothesize that YAP1 plays a role in proliferation and estrogen secretion of GCs. In the current study, we examined the expression of the Hippo signaling pathway in bovine ovaries and determined whether it was important for GC proliferation and estrogen production. Mammalian STE20-like protein kinase 1 (MST1) and large tumor suppressor kinase 2 (LATS2) were identified as prominent upstream components of the Hippo pathway expressed in granulosa and theca cells of the follicle and large and small cells of the corpus luteum. Immunohistochemistry revealed that YAP1 was localized to the nucleus of growing follicles. In vitro, nuclear localization of the downstream Hippo signaling effector proteins YAP1 and transcriptional co-activator with PDZ-binding motif (TAZ) was inversely correlated with GC density, with greater nuclear localization under conditions of low cell density. Treatment with verteporfin and siRNA targeting YAP1 or TAZ revealed a critical role for these transcriptional co-activators in GC proliferation. Furthermore, knockdown of YAP1 in GCs inhibited follicle-stimulating hormone (FSH)-induced estradiol biosynthesis. The data indicate that Hippo pathway transcription co-activators YAP1/TAZ play an important role in GC proliferation and estradiol synthesis, two processes necessary for maintaining normal follicle development.

scholarly journals MAML1/2 promote YAP/TAZ nuclear localization and tumorigenesis

2020 ◽  
Vol 117 (24) ◽  
pp. 13529-13540 ◽  
Author(s):  
Jiyoung Kim ◽  
Hyeryun Kwon ◽  
You Keun Shin ◽  
Gahyeon Song ◽  
Taebok Lee ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Messenger Rna ◽  
Molecular Mechanisms ◽  
Nuclear Translocation ◽  
Human Cancer ◽  
Hippo Pathway ◽  
Ectopic Expression ◽  
Dependent Manner ◽  
The Hippo Pathway

The Hippo pathway plays a pivotal role in tissue homeostasis and tumor suppression. YAP and TAZ are downstream effectors of the Hippo pathway, and their activities are tightly suppressed by phosphorylation-dependent cytoplasmic retention. However, the molecular mechanisms governing YAP/TAZ nuclear localization have not been fully elucidated. Here, we report that Mastermind-like 1 and 2 (MAML1/2) are indispensable for YAP/TAZ nuclear localization and transcriptional activities. Ectopic expression or depletion of MAML1/2 induces nuclear translocation or cytoplasmic retention of YAP/TAZ, respectively. Additionally, mutation of the MAML nuclear localization signal, as well as its YAP/TAZ interacting region, both abolish nuclear localization and transcriptional activity of YAP/TAZ. Importantly, we demonstrate that the level ofMAML1messenger RNA (mRNA) is regulated by microRNA-30c (miR-30c) in a cell-density-dependent manner. In vivo and clinical results suggest that MAML potentiates YAP/TAZ oncogenic function and positively correlates with YAP/TAZ activation in human cancer patients, suggesting pathological relevance in the context of cancer development. Overall, our study not only provides mechanistic insight into the regulation of YAP/TAZ subcellular localization, but it also strongly suggests that the miR30c–MAML–YAP/TAZ axis is a potential therapeutic target for developing novel cancer treatments.

scholarly journals Functional complexes between YAP2 and ZO-2 are PDZ domain-dependent, and regulate YAP2 nuclear localization and signalling1

2010 ◽  
Vol 432 (3) ◽  
pp. 461-478 ◽  
Author(s):  
Tsutomu Oka ◽  
Eline Remue ◽  
Kris Meerschaert ◽  
Berlinda Vanloo ◽  
Ciska Boucherie ◽  
...  
Keyword(s):  
Nuclear Localization ◽  
Mammalian Cells ◽  
Nuclear Translocation ◽  
Hippo Pathway ◽  
Pdz Domain ◽  
Binding Motif ◽  
Ww Domains ◽  
C Terminus ◽  
Junction Protein ◽  
The Hippo Pathway

The Hippo pathway regulates the size of organs by controlling two opposing processes: proliferation and apoptosis. YAP2 (Yes kinase-associated protein 2), one of the three isoforms of YAP, is a WW domain-containing transcriptional co-activator that acts as the effector of the Hippo pathway in mammalian cells. In addition to WW domains, YAP2 has a PDZ-binding motif at its C-terminus. We reported previously that this motif was necessary for YAP2 localization in the nucleus and for promoting cell detachment and apoptosis. In the present study, we show that the tight junction protein ZO (zonula occludens)-2 uses its first PDZ domain to form a complex with YAP2. The endogenous ZO-2 and YAP2 proteins co-localize in the nucleus. We also found that ZO-2 facilitates the nuclear localization and pro-apoptotic function of YAP2, and that this activity of ZO-2 is PDZ-domain-dependent. The present paper is the first report on a PDZ-based nuclear translocation mechanism. Moreover, since the Hippo pathway acts as a tumour suppressor pathway, the YAP2–ZO-2 complex could represent a target for cancer therapy.

scholarly journals The Hippo pathway effectors YAP and TAZ promote cell growth by modulating amino acid signaling to mTORC1

Cell Research ◽  
2015 ◽  
Vol 25 (12) ◽  
pp. 1299-1313 ◽  
Author(s):  
Carsten Gram Hansen ◽  
Yuen Lam Dora Ng ◽  
Wai-Ling Macrina Lam ◽  
Steven W Plouffe ◽  
Kun-Liang Guan
Keyword(s):  
Amino Acid ◽  
Cell Growth ◽  
Hippo Pathway ◽  
The Hippo Pathway ◽  
Amino Acid Signaling

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

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.

Recombinant Variants of Tissue-Type Plasminogen Activator Containing Amino Acid Substitutions in the Finger Domain

1992 ◽  
Vol 68 (06) ◽  
pp. 672-677 ◽  
Author(s):  
Hitoshi Yahara ◽  
Keiji Matsumoto ◽  
Hiroyuki Maruyama ◽  
Tetsuya Nagaoka ◽  
Yasuhiro Ikenaka ◽  
...  
Keyword(s):  
Amino Acid ◽  
Plasminogen Activator ◽  
Half Life ◽  
Tissue Type ◽  
Clot Lysis ◽  
Amino Acid Substitutions ◽  
Wild Type ◽  
Plasma Clot ◽  
Tissue Type Plasminogen Activator ◽  
Type Plasminogen Activator

SummaryTissue-type plasminogen activator (t-PA) is a fibrin-specific agent which has been used to treat acute myocardial infarction. In an attempt to clarify the determinants for its rapid clearance in vivo and high affinity for fibrin clots, we produced five variants containing amino acid substitutions in the finger domain, at amino acid residues 7–9, 10–14, 15–19, 28–33, and 37–42. All the variants had a prolonged half-life and a decreased affinity for fibrin of various degrees. The 37–42 variant demonstrated about a 6-fold longer half-life with a lower affinity for fibrin. Human plasma clot lysis assay estimated the fibrinolytic activity of the 37–42 variant to be 1.4-fold less effective than that of the wild-type rt-PA. In a rabbit jugular vein clot lysis model, doses of 1.0 and 0.15 mg/kg were required for about 70% lysis in the wild-type and 37–42 variant, respectively. Fibrinogen was degraded only when the wild-type rt-PA was administered at a dose of 1.0 mg/kg. These findings suggest that the 37–42 variant can be employed at a lower dosage and that it is a more fibrin-specific thrombolytic agent than the wild-type rt-PA.

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