scholarly journals The nonreceptor tyrosine kinase c-Src attenuates SCF(β-TrCP) E3-ligase activity abrogating Taz proteasomal degradation

2017 ◽  
Vol 114 (7) ◽  
pp. 1678-1683 ◽  
Author(s):  
Matan Shanzer ◽  
Julia Adler ◽  
Inna Ricardo-Lax ◽  
Nina Reuven ◽  
Yosef Shaul
Keyword(s):  
Tyrosine Kinase ◽  
Hippo Pathway ◽  
E3 Ligase ◽  
Proteasomal Degradation ◽  
T Antigen ◽  
Binding Motif ◽  
Src Tyrosine Kinase ◽  
Nonreceptor Tyrosine Kinase ◽  
Kinase C ◽  
The Hippo Pathway

The polyomavirus middle T antigen (PyMT) oncogene activates the cellular nonreceptor tyrosine kinase c-Src and recruits the Hippo pathway effectors, Yap (yes-associated protein) and Taz (transcriptional coactivator with PDZ-binding motif), as key steps in oncogenesis. Yap and Taz are transcription coactivators shuttling from the cytoplasm to the nucleus. The Hippo pathway kinase Lats1/2 (large tumor suppressor homolog) reduces Yap/Taz nuclear localization and minimizes their cytoplasmic levels by facilitating their ubiquitination by the E3 ligase SCF(β-TrCP). In contrast, PyMT increases the cytoplasmic Taz level. Here we show that this unique PyMT behavior is mediated by Src. We demonstrate that PyMT-induced Src activation inhibits degradation of both wild-type and tyrosine-less Taz, ruling out Taz modification as a mechanism of escaping degradation. Instead, we found that Src attenuates the SCF(β-TrCP) E3-ligase activity in blunting Taz proteasomal degradation. The role of Src in rescuing Taz from TrCP-mediated degradation gives rise to higher cell proliferation under dense cell culture. Finally, IkB (NF-kappa-B inhibitor), a known substrate of β-TrCP, was rescued by Src, suggesting a wider effect of Src on β-TrCP substrates. These findings introduce the Src tyrosine kinase as a regulator of SCF(β-TrCP).

The Nedd4-like ubiquitin E3 ligases target angiomotin/p130 to ubiquitin-dependent degradation

2012 ◽  
Vol 444 (2) ◽  
pp. 279-289 ◽  
Author(s):  
Chenji Wang ◽  
Jian An ◽  
Pingzhao Zhang ◽  
Chen Xu ◽  
Kun Gao ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
State Level ◽  
Proteasomal Degradation ◽  
Binding Motif ◽  
Ww Domains ◽  
E3 Ligases ◽  
Tight Junction Formation ◽  
Junction Formation ◽  
The Hippo Pathway

AMOT (angiomotin) is a membrane-associated protein that is expressed in ECs (endothelial cells) and controls migration, TJ (tight junction) formation, cell polarity and angiogenesis. Recent studies have revealed that AMOT and two AMOT-like proteins, AMOTL1 and AMOTL2, play critical roles in the Hippo pathway by regulating the subcellular localization of the co-activators YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif). However, it has been unclear how AMOT is regulated. In the present study, we report that AMOT undergoes proteasomal degradation. We identify three members of Nedd4 (neural-precursor-cell-expressed developmentally down-regulated)-like ubiquitin E3 ligases, Nedd4, Nedd4-2 and Itch, as the ubiquitin E3 ligases for the long isoform of AMOT, AMOT/p130. We demonstrate that Nedd4, Nedd4-2 and Itch mediate poly-ubiquitination of AMOT/p130 in vivo. Overexpression of Nedd4, Nedd4-2 or Itch leads to AMOT/p130 proteasomal degradation. Knockdown of Nedd4, Nedd4-2 and Itch causes an accumulation of steady-state level of AMOT/p130. We also show that three L/P-PXY motifs of AMOT/p130 and the WW domains of Nedd4 mediate their interaction. Furthermore, Nedd4-like ubiquitin E3 ligases might compete with YAP for the binding to AMOT/p130, and subsequently targeting AMOT/p130 for ubiquitin-dependent degradation. Together, these observations reveal a novel post-translational regulatory mechanism of AMOT/p130.

scholarly journals YAP and endothelin-1 signaling: an emerging alliance in cancer

2021 ◽  
Vol 40 (1) ◽  
Author(s):  
Piera Tocci ◽  
Giovanni Blandino ◽  
Anna Bagnato
Keyword(s):  
Signaling Pathways ◽  
Cell Fate ◽  
Therapeutic Option ◽  
Hippo Pathway ◽  
Signaling Network ◽  
Nuclear Accumulation ◽  
Binding Motif ◽  
Mutant P53 ◽  
Endothelin 1 ◽  
The Hippo Pathway

AbstractThe rational making the G protein-coupled receptors (GPCR) the centerpiece of targeted therapies is fueled by the awareness that GPCR-initiated signaling acts as pivotal driver of the early stages of progression in a broad landscape of human malignancies. The endothelin-1 (ET-1) receptors (ET-1R), known as ETA receptor (ETAR) and ETB receptor (ETBR) that belong to the GPCR superfamily, affect both cancer initiation and progression in a variety of cancer types. By the cross-talking with multiple signaling pathways mainly through the scaffold protein β-arrestin1 (β-arr1), ET-1R axis cooperates with an array of molecular determinants, including transcription factors and co-factors, strongly affecting tumor cell fate and behavior. In this scenario, recent findings shed light on the interplay between ET-1 and the Hippo pathway. In ETAR highly expressing tumors ET-1 axis induces the de-phosphorylation and nuclear accumulation of the Hippo pathway downstream effectors, the paralogous transcriptional cofactors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). Recent evidence have discovered that ET-1R/β-arr1 axis instigates a transcriptional interplay involving YAP and mutant p53 proteins, which share a common gene signature and cooperate in a oncogenic signaling network. Mechanistically, YAP and mutp53 are enrolled in nuclear complexes that turn on a highly selective YAP/mutp53-dependent transcriptional response. Notably, ET-1R blockade by the FDA approved dual ET-1 receptor antagonist macitentan interferes with ET-1R/YAP/mutp53 signaling interplay, through the simultaneous suppression of YAP and mutp53 functions, hampering metastasis and therapy resistance. Based on these evidences, we aim to review the recent findings linking the GPCR signaling, as for ET-1R, to YAP/TAZ signaling, underlining the clinical relevance of the blockade of such signaling network in the tumor and microenvironmental contexts. In particular, we debate the clinical implications regarding the use of dual ET-1R antagonists to blunt gain of function activity of mutant p53 proteins and thereby considering them as a potential therapeutic option for mutant p53 cancers. The identification of ET-1R/β-arr1-intertwined and bi-directional signaling pathways as targetable vulnerabilities, may open new therapeutic approaches able to disable the ET-1R-orchestrated YAP/mutp53 signaling network in both tumor and stromal cells and concurrently sensitizes to high-efficacy combined therapeutics.

scholarly journals Tubule-Specific Mst1/2 Deficiency Induces CKD via YAP and Non-YAP Mechanisms

2020 ◽  
Vol 31 (5) ◽  
pp. 946-961 ◽  
Author(s):  
Chunhua Xu ◽  
Li Wang ◽  
Yu Zhang ◽  
Wenling Li ◽  
Jinhong Li ◽  
...  
Keyword(s):  
Kidney Development ◽  
Collecting Duct ◽  
Hippo Pathway ◽  
Binding Motif ◽  
Renal Tubules ◽  
Double Knockout ◽  
Core Components ◽  
Collecting Duct Cells ◽  
Medullary Collecting Duct ◽  
The Hippo Pathway

BackgroundThe serine/threonine kinases MST1 and MST2 are core components of the Hippo pathway, which has been found to be critically involved in embryonic kidney development. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are the pathway’s main effectors. However, the biologic functions of the Hippo/YAP pathway in adult kidneys are not well understood, and the functional role of MST1 and MST2 in the kidney has not been studied.MethodsWe used immunohistochemistry to examine expression in mouse kidneys of MST1 and MST2, homologs of Hippo in Drosophila. We generated mice with tubule-specific double knockout of Mst1 and Mst2 or triple knockout of Mst1, Mst2, and Yap. PCR array and mouse inner medullary collecting duct cells were used to identify the primary target of Mst1/Mst2 deficiency.ResultsMST1 and MST2 were predominantly expressed in the tubular epithelial cells of adult kidneys. Deletion of Mst1/Mst2 in renal tubules increased activity of YAP but not TAZ. The kidneys of mutant mice showed progressive inflammation, tubular and glomerular damage, fibrosis, and functional impairment; these phenotypes were largely rescued by deletion of Yap in renal tubules. TNF-α expression was induced via both YAP-dependent and YAP-independent mechanisms, and TNF-α and YAP amplified the signaling activities of each other in the tubules of kidneys with double knockout of Mst1/Mst2.ConclusionsOur findings show that tubular Mst1/Mst2 deficiency leads to CKD through both the YAP and non-YAP pathways and that tubular YAP activation induces renal fibrosis. The pathogenesis seems to involve the reciprocal stimulation of TNF-α and YAP signaling activities.

scholarly journals STK38 promotes ATM activation by acting as a reader of histone H4 ufmylation

2020 ◽  
Vol 6 (23) ◽  
pp. eaax8214 ◽  
Author(s):  
Bo Qin ◽  
Jia Yu ◽  
Somaira Nowsheen ◽  
Fei Zhao ◽  
Liewei Wang ◽  
...  
Keyword(s):  
Dna Damage ◽  
Hippo Pathway ◽  
Double Strand Breaks ◽  
Binding Motif ◽  
Histone H4 ◽  
Ataxia Telangiectasia Mutated ◽  
Independent Manner ◽  
Strand Breaks ◽  
Dna Damage Signaling ◽  
The Hippo Pathway

The ATM (ataxia-telangiectasia mutated) kinase is rapidly activated following DNA damage and phosphorylates its downstream targets to launch DDR signaling. Recently, we and others showed that UFM1 signaling promotes ATM activation. We further discovered that monoufmylation of histone H4 at Lys31 by UFM1-specific ligase 1 (UFL1) is an important step in the amplification of ATM activation. However, how monoufmylated H4 enhances ATM activation is still unknown. Here, we report STK38, a kinase in the Hippo pathway, serves as a reader for histone H4 ufmylation to promote ATM activation in a kinase-independent manner. STK38 contains a potential UFM1 binding motif which recognizes ufmylated H4 and recruits the SUV39H1 to the double-strand breaks, resulting in H3K9 trimethylation and Tip60 activation to promote ATM activation. Together, STK38 is a previously unknown player in DNA damage signaling and functions as a reader of monoufmylated H4 at Lys31 to promote ATM activation.

scholarly journals Differential regulation of the Hippo pathway by adherens junctions and apical–basal cell polarity modules

2015 ◽  
Vol 112 (6) ◽  
pp. 1785-1790 ◽  
Author(s):  
Chih-Chao Yang ◽  
Hillary K. Graves ◽  
Ivan M. Moya ◽  
Chunyao Tao ◽  
Fisun Hamaratoglu ◽  
...  
Keyword(s):  
Cell Polarity ◽  
Basal Cell ◽  
Mammalian Cells ◽  
Adherens Junctions ◽  
Hippo Pathway ◽  
Tumor Formation ◽  
Nuclear Accumulation ◽  
Binding Motif ◽  
Downstream Effectors ◽  
The Hippo Pathway

Adherens junctions (AJs) and cell polarity complexes are key players in the establishment and maintenance of apical–basal cell polarity. Loss of AJs or basolateral polarity components promotes tumor formation and metastasis. Recent studies in vertebrate models show that loss of AJs or loss of the basolateral component Scribble (Scrib) cause deregulation of the Hippo tumor suppressor pathway and hyperactivation of its downstream effectors Yes-associated protein (YAP) and Transcriptional coactivator with PDZ-binding motif (TAZ). However, whether AJs and Scrib act through the same or independent mechanisms to regulate Hippo pathway activity is not known. Here, we dissect how disruption of AJs or loss of basolateral components affect the activity of the Drosophila YAP homolog Yorkie (Yki) during imaginal disc development. Surprisingly, disruption of AJs and loss of basolateral proteins produced very different effects on Yki activity. Yki activity was cell-autonomously decreased but non–cell-autonomously elevated in tissues where the AJ components E-cadherin (E-cad) or α-catenin (α-cat) were knocked down. In contrast, scrib knockdown caused a predominantly cell-autonomous activation of Yki. Moreover, disruption of AJs or basolateral proteins had different effects on cell polarity and tissue size. Simultaneous knockdown of α-cat and scrib induced both cell-autonomous and non–cell-autonomous Yki activity. In mammalian cells, knockdown of E-cad or α-cat caused nuclear accumulation and activation of YAP without overt effects on Scrib localization and vice versa. Therefore, our results indicate the existence of multiple, genetically separable inputs from AJs and cell polarity complexes into Yki/YAP regulation.

scholarly journals Modulation of the F-actin cytoskeleton by c-Abl tyrosine kinase in cell spreading and neurite extension

2002 ◽  
Vol 156 (5) ◽  
pp. 879-892 ◽  
Author(s):  
Pamela J. Woodring ◽  
E. David Litwack ◽  
Dennis D.M. O'Leary ◽  
Ginger R. Lucero ◽  
Jean Y.J. Wang ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Actin Cytoskeleton ◽  
Cortical Neurons ◽  
Cell Attachment ◽  
Actin Binding ◽  
Src Tyrosine Kinase ◽  
Reciprocal Regulation ◽  
Nonreceptor Tyrosine Kinase ◽  
Abl Tyrosine Kinase ◽  
Cytoskeleton Dynamics

The nonreceptor tyrosine kinase encoded by the c-Abl gene has the unique feature of an F-actin binding domain (FABD). Purified c-Abl tyrosine kinase is inhibited by F-actin, and this inhibition can be relieved through mutation of its FABD. The c-Abl kinase is activated by physiological signals that also regulate the actin cytoskeleton. We show here that c-Abl stimulated the formation of actin microspikes in fibroblasts spreading on fibronectin. This function of c-Abl is dependent on kinase activity and is not shared by c-Src tyrosine kinase. The Abl-dependent F-actin microspikes occurred under conditions where the Rho-family GTPases were inhibited. The FABD-mutated c-Abl, which is active in detached fibroblasts, stimulated F-actin microspikes independent of cell attachment. Moreover, FABD-mutated c-Abl stimulated the formation of F-actin branches in neurites of rat embryonic cortical neurons. The reciprocal regulation between F-actin and the c-Abl tyrosine kinase may provide a self-limiting mechanism in the control of actin cytoskeleton dynamics.

Inactivation of c-Yes tyrosine kinase by elevation of intracellular calcium levels

1993 ◽  
Vol 13 (12) ◽  
pp. 7507-7514
Author(s):  
Y Zhao ◽  
H Uyttendaele ◽  
J G Krueger ◽  
M Sudol ◽  
H Hanafusa
Keyword(s):  
Tyrosine Kinase ◽  
Intracellular Calcium ◽  
Protein Tyrosine Phosphatases ◽  
Cell Extract ◽  
Cellular Proteins ◽  
Src Tyrosine Kinase ◽  
Protein Levels ◽  
Kinase C ◽  
Dependent Inactivation

We have previously shown that the c-Src tyrosine kinase is activated four- to fivefold when cultured keratinocytes differentiate following the elevation of intracellular calcium levels. In contrast to c-Src, another Src family tyrosine kinase, c-Yes, was rapidly inactivated in these same cells, despite its marked similarity in structure and enzymatic activity to c-Src. The inactivation of c-Yes was independent of the protein kinase C pathway, which is usually activated by elevation of intracellular calcium levels. The protein levels of c-Src and c-Yes were not altered, but the phosphotyrosine content of both proteins was greatly reduced. As has been demonstrated for c-Src, in vitro dephosphorylation of c-Yes by incubation with protein tyrosine phosphatases also resulted in its activation, not inactivation. In vitro reconstitution experiments showed that c-Yes can be inactivated by preincubation with a Ca(2+)-supplemented cell extract and that this inhibition was reversed by the addition of EGTA [ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid]. Gradient sedimentation of cell lysates showed that in cells treated with calcium and ionophore, c-Yes formed complexes with two distinct cellular proteins, whereas similar complexes were not seen in c-Src immunoprecipitates. One of these two proteins has the ability to inhibit c-Yes kinase activity in vitro. Finally, the Ca(2+)-dependent inactivation of c-Yes was observed in kidney tubular cells and fibroblasts, suggesting that the Ca(2+)-dependent regulation of c-Yes tyrosine kinase is not unique to keratinocytes. We postulate that c-Yes is inactivated through a Ca2+ -dependent association with cellular proteins, which seems to override its activation resulting from tyrosine dephosphorylation.

scholarly journals Repurposing of Drugs Targeting YAP-TEAD Functions

Cancers ◽  
2018 ◽  
Vol 10 (9) ◽  
pp. 329 ◽  
Author(s):  
Gian Elisi ◽  
Matteo Santucci ◽  
Domenico D’Arca ◽  
Angela Lauriola ◽  
Gaetano Marverti ◽  
...  
Keyword(s):  
Hippo Pathway ◽  
Drug Repurposing ◽  
Binding Motif ◽  
Discovery Process ◽  
Molecular Tools ◽  
Drug Discovery Process ◽  
Lead Compounds ◽  
Investigational Drugs ◽  
The Hippo Pathway ◽  
Cell Signaling Pathways

Drug repurposing is a fast and consolidated approach for the research of new active compounds bypassing the long streamline of the drug discovery process. Several drugs in clinical practice have been reported for modulating the major Hippo pathway’s terminal effectors, namely YAP (Yes1-associated protein), TAZ (transcriptional co-activator with PDZ-binding motif) and TEAD (transcriptional enhanced associate domains), which are directly involved in the regulation of cell growth and tissue homeostasis. Since this pathway is known to have many cross-talking phenomena with cell signaling pathways, many efforts have been made to understand its importance in oncology. Moreover, this could be relevant to obtain new molecular tools and potential therapeutic assets. In this review, we discuss the main mechanisms of action of the best-known compounds, clinically approved or investigational drugs, able to cross-talk and modulate the Hippo pathway, as an attractive strategy for the discovery of new potential lead compounds.

scholarly journals Cyclopeptide RA-V Inhibits Organ Enlargement and Tumorigenesis Induced by YAP Activation

Cancers ◽  
2018 ◽  
Vol 10 (11) ◽  
pp. 449 ◽  
Author(s):  
Xinyan Ji ◽  
Lihua Song ◽  
Li Sheng ◽  
Anhui Gao ◽  
Yang Zhao ◽  
...  
Keyword(s):  
Target Genes ◽  
Hippo Pathway ◽  
Specific Inhibitor ◽  
Drug Candidate ◽  
Binding Motif ◽  
Mrna Levels ◽  
Transcriptional Coactivator ◽  
Genetic Inactivation ◽  
Liver Enlargement ◽  
The Hippo Pathway

The Hippo pathway restricts organ size during development and its inactivation plays a crucial role in cancer. Yes-associated protein (YAP) and its paralog transcriptional coactivator with PSD-95/Dlg/ZO-1 (PDZ)-binding motif (TAZ) are transcription co-activators and effectors of the Hippo pathway mediating aberrant enlargement of organs and tumor growth upon Hippo pathway inactivation. It has been demonstrated that genetic inactivation of YAP could be an effective approach to inhibit tumorigenesis. In order to identify pharmacological inhibitors of YAP, we screened a library of 52,683 compounds using a YAP-specific reporter assay. In this screen we identified cyclopeptide RA-V (deoxybouvardin) as a specific inhibitor of YAP and TAZ but not other reporters. Unexpectedly, later experiments demonstrated that RA-V represses the protein but not mRNA levels of YAP target genes. Nevertheless, RA-V strongly blocks liver enlargement induced by Mst1/2 knockout. Furthermore, RA-V not only inhibits liver tumorigenesis induced by YAP activation, but also induces regression of established tumors. We found that RA-V inhibits dedifferentiation and proliferation, while inducing apoptosis of hepatocytes. Furthermore, RA-V also induces apoptosis and inhibits proliferation of macrophages in the microenvironment, which are essential for YAP-induced tumorigenesis. RA-V is thus a drug candidate for cancers involving YAP/TAZ activation.

Sign in / Sign up

Export Citation Format

Share Document