scholarly journals The dynamic mechanism of RASSF5 and MST kinase activation by Ras

2017 ◽  
Vol 19 (9) ◽  
pp. 6470-6480 ◽  
Author(s):  
Tsung-Jen Liao ◽  
Hyunbum Jang ◽  
Chung-Jung Tsai ◽  
David Fushman ◽  
Ruth Nussinov
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
Dynamic Mechanism ◽  
Kinase Activation ◽  
The Hippo Pathway

As a tumor suppressor, RASSF5 (NORE1A) activates MST1/2 thereby modulating the Hippo pathway.

scholarly journals Yes-Associated Protein 1 Is a Novel Calcium Sensing Receptor Target in Human Parathyroid Tumors

2021 ◽  
Vol 22 (4) ◽  
pp. 2016
Author(s):  
Giulia Stefania Tavanti ◽  
Chiara Verdelli ◽  
Annamaria Morotti ◽  
Paola Maroni ◽  
Vito Guarnieri ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
Human Tumor ◽  
Parathyroid Glands ◽  
Nuclear Accumulation ◽  
Calcium Sensing Receptor ◽  
Large Tumor ◽  
Parathyroid Tumors ◽  
Calcium Sensing ◽  
The Hippo Pathway

The Hippo pathway is involved in human tumorigenesis and tissue repair. Here, we investigated the Hippo coactivator Yes-associated protein 1 (YAP1) and the kinase large tumor suppressor 1/2 (LATS1/2) in tumors of the parathyroid glands, which are almost invariably associated with primary hyperparathyroidism. Compared with normal parathyroid glands, parathyroid adenomas (PAds) and carcinomas show variably but reduced nuclear YAP1 expression. The kinase LATS1/2, which phosphorylates YAP1 thus promoting its degradation, was also variably reduced in PAds. Further, YAP1 silencing reduces the expression of the key parathyroid oncosuppressor multiple endocrine neoplasia type 1(MEN1), while MEN1 silencing increases YAP1 expression. Treatment of patient-derived PAds-primary cell cultures and Human embryonic kidney 293A (HEK293A) cells expressing the calcium-sensing receptor (CASR) with the CASR agonist R568 induces YAP1 nuclear accumulation. This effect was prevented by the incubation of the cells with RhoA/Rho-associated coiled-coil-containing protein kinase (ROCK) inhibitors Y27632 and H1152. Lastly, CASR activation increased the expression of the YAP1 gene targets CYR61, CTGF, and WNT5A, and this effect was blunted by YAP1 silencing. Concluding, here we provide preliminary evidence of the involvement of the Hippo pathway in human tumor parathyroid cells and of the existence of a CASR-ROCK-YAP1 axis. We propose a tumor suppressor role for YAP1 and LATS1/2 in parathyroid tumors.

scholarly journals α-Arrestin ARRDC3 tumor suppressor function is linked to GPCR-induced TAZ activation and breast cancer metastasis

2021 ◽  
Vol 134 (8) ◽  
Author(s):  
Aleena K. S. Arakaki ◽  
Wen-An Pan ◽  
Helen Wedegaertner ◽  
Ivette Roca-Mercado ◽  
Logan Chinn ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Suppressor ◽  
Cancer Progression ◽  
Cancer Metastasis ◽  
Hippo Pathway ◽  
Breast Cancer Metastasis ◽  
Migration And Invasion ◽  
Hippo Signaling ◽  
The Hippo Pathway

ABSTRACT The α-arrestin domain containing protein 3 (ARRDC3) is a tumor suppressor in triple-negative breast carcinoma (TNBC), a highly metastatic subtype of breast cancer that lacks targeted therapies. Thus, understanding the mechanisms and targets of ARRDC3 in TNBC is important. ARRDC3 regulates trafficking of protease-activated receptor 1 (PAR1, also known as F2R), a G-protein-coupled receptor (GPCR) implicated in breast cancer metastasis. Loss of ARRDC3 causes overexpression of PAR1 and aberrant signaling. Moreover, dysregulation of GPCR-induced Hippo signaling is associated with breast cancer progression. However, the mechanisms responsible for Hippo dysregulation remain unknown. Here, we report that the Hippo pathway transcriptional co-activator TAZ (also known as WWTR1) is the major effector of GPCR signaling and is required for TNBC migration and invasion. Additionally, ARRDC3 suppresses PAR1-induced Hippo signaling via sequestration of TAZ, which occurs independently of ARRDC3-regulated PAR1 trafficking. The ARRDC3 C-terminal PPXY motifs and TAZ WW domain are crucial for this interaction and are required for suppression of TNBC migration and lung metastasis in vivo. These studies are the first to demonstrate a role for ARRDC3 in regulating GPCR-induced TAZ activity in TNBC and reveal multi-faceted tumor suppressor functions of ARRDC3. This article has an associated First Person interview with the first author of the paper.

Abstract SY26-03: Tumor suppressor crosstalk: Modulation of p53 activity by the Hippo pathway

2016 ◽  
Author(s):  
Moshe Oren ◽  
Noa Furth ◽  
Noa Bossel Ben-Moshe ◽  
Ziv Porat ◽  
Eytan Domany ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
The Hippo Pathway

scholarly journals SAV1 promotes Hippo kinase activation through antagonizing the PP2A phosphatase STRIPAK

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Sung Jun Bae ◽  
Lisheng Ni ◽  
Adam Osinski ◽  
Diana R Tomchick ◽  
Chad A Brautigam ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Hippo Pathway ◽  
Tissue Growth ◽  
Activation Loop ◽  
Hippo Signaling ◽  
Ww Domains ◽  
Kinase Activation ◽  
Genetic Ablation ◽  
Kinase Cascade ◽  
The Hippo Pathway

The Hippo pathway controls tissue growth and homeostasis through a central MST-LATS kinase cascade. The scaffold protein SAV1 promotes the activation of this kinase cascade, but the molecular mechanisms remain unknown. Here, we discover SAV1-mediated inhibition of the PP2A complex STRIPAKSLMAP as a key mechanism of MST1/2 activation. SLMAP binding to autophosphorylated MST2 linker recruits STRIPAK and promotes PP2A-mediated dephosphorylation of MST2 at the activation loop. Our structural and biochemical studies reveal that SAV1 and MST2 heterodimerize through their SARAH domains. Two SAV1–MST2 heterodimers further dimerize through SAV1 WW domains to form a heterotetramer, in which MST2 undergoes trans-autophosphorylation. SAV1 directly binds to STRIPAK and inhibits its phosphatase activity, protecting MST2 activation-loop phosphorylation. Genetic ablation of SLMAP in human cells leads to spontaneous activation of the Hippo pathway and alleviates the need for SAV1 in Hippo signaling. Thus, SAV1 promotes Hippo activation through counteracting the STRIPAKSLMAP PP2A phosphatase complex.

scholarly journals Activation mechanisms of the Hippo kinase signaling cascade

2018 ◽  
Vol 38 (4) ◽  
Author(s):  
Sung Jun Bae ◽  
Xuelian Luo
Keyword(s):  
Hippo Pathway ◽  
Adaptor Proteins ◽  
Tissue Growth ◽  
Fine Tuning ◽  
Hippo Signaling ◽  
Kinase Activation ◽  
The Core ◽  
Activation Mechanisms ◽  
Kinase Cascade ◽  
The Hippo Pathway

First discovered two decades ago through genetic screens in Drosophila, the Hippo pathway has been shown to be conserved in metazoans and controls organ size and tissue homeostasis through regulating the balance between cell proliferation and apoptosis. Dysregulation of the Hippo pathway leads to aberrant tissue growth and tumorigenesis. Extensive studies in Drosophila and mammals have identified the core components of Hippo signaling, which form a central kinase cascade to ultimately control gene expression. Here, we review recent structural, biochemical, and cellular studies that have revealed intricate phosphorylation-dependent mechanisms in regulating the formation and activation of the core kinase complex in the Hippo pathway. These studies have established the dimerization-mediated activation of the Hippo kinase (mammalian Ste20-like 1 and 2 (MST1/2) in mammals), the dynamic scaffolding and allosteric roles of adaptor proteins in downstream kinase activation, and the importance of multisite linker autophosphorylation by Hippo and MST1/2 in fine-tuning the signaling strength and robustness of the Hippo pathway. We highlight the gaps in our knowledge in this field that will require further mechanistic studies.

scholarly journals Loss of the FAT1 Tumor Suppressor Promotes Resistance to CDK4/6 Inhibitors via the Hippo Pathway

Cancer Cell ◽  
2018 ◽  
Vol 34 (6) ◽  
pp. 893-905.e8 ◽  
Author(s):  
Zhiqiang Li ◽  
Pedram Razavi ◽  
Qing Li ◽  
Weiyi Toy ◽  
Bo Liu ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
The Hippo Pathway

scholarly journals Deubiquitylase USP9X suppresses tumorigenesis by stabilizing large tumor suppressor kinase 2 (LATS2) in the Hippo pathway

2017 ◽  
Vol 293 (4) ◽  
pp. 1178-1191 ◽  
Author(s):  
Chu Zhu ◽  
Xinyan Ji ◽  
Haitao Zhang ◽  
Qi Zhou ◽  
Xiaolei Cao ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Hippo Pathway ◽  
Large Tumor ◽  
The Hippo Pathway ◽  
Large Tumor Suppressor

scholarly journals Extracellular matrix stiffness regulates degradation of the Hippo kinase MST2 via SCF βTrCP

2021 ◽  
Author(s):  
Ana Paula Zen Petisco Fiore ◽  
Ana Maria Rodrigues da Silva ◽  
Helder Veras Ribeiro Filho ◽  
Antonio Carlos Manucci ◽  
Pedro de Freitas Ribeiro ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Hippo Pathway ◽  
Site Directed Mutagenesis ◽  
Kinase Activation ◽  
Tumor Microenvironments ◽  
Extracellular Matrix Stiffness ◽  
Integrin Linked Kinase ◽  
Tensional Homeostasis ◽  
The Hippo Pathway ◽  
Human Breast Epithelial Cells

AbstractTumor microenvironments display disrupted mechanical properties, including altered extracellular matrix (ECM) rigidity. ECM stiffening perturbs cell tensional homeostasis resulting in activation of mechanosensing transcriptional co-activators, such as the Hippo pathway effectors YAP and TAZ. The Hippo pathway plays central roles in development and tumorigenesis, but how the proteostasis of the Hippo kinase MST2 is regulated remains unknown. We show that MST2 levels decrease upon changes in ECM rigidity via proteasome degradation. MST2 degradation is enhanced in human breast epithelial cells that are cultured in stiffer microenvironments due to integrin and integrin-linked kinase activation. MST2 knockdown resulted in increased nucleus-to-cytoplasm ratio of YAP, increased proliferation rates in a soft microenvironment and F-actin alignment in cells cultured in intermediate stiffness. We found that MST2 is ubiquitinated by the SCFβTrCP ubiquitin ligase, and site-directed mutagenesis combined with computational molecular dynamics studies revealed that βTrCP binds MST2 via a noncanonical degradation motif. Our study uncovers the underlying biochemical mechanisms controlling MST2 degradation and demonstrates how alterations in the microenvironment rigidity regulate the proteostasis of a central Hippo pathway component.

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