Extracellular signal-regulated kinase (ERK) is a part of the mitogen-activated protein kinase (MAPK) signaling pathway which allows the transduction of various cellular signals to final effectors and regulation of elementary cellular processes. Deregulation of the MAPK signaling occurs under many pathological conditions including neurodegenerative disorders, metabolic syndromes and cancers. Targeted inhibition of individual kinases of the MAPK signaling pathway using synthetic compounds represents a promising way to effective anti-cancer therapy. Cross-talk of the MAPK signaling pathway with other proteins and signaling pathways have a crucial impact on clinical outcomes of targeted therapies and plays important role during development of drug resistance in cancers. We discuss cross-talk of the MAPK/ERK signaling pathway with other signaling pathways, in particular interplay with the Hippo/MST pathway. We demonstrate the mechanism of cell death induction shared between MAPK/ERK and Hippo/MST signaling pathways and discuss the potential of combination targeting of these pathways in the development of more effective anti-cancer therapies.

• Klíčová slova
• ERK, Hippo, MAPK, MST, PI3K, YAP, apoptosis, cancer, caspase, inhibitors, natural compounds, therapy,
• MeSH
• antitumorózní látky terapeutické užití   MeSH
• extracelulárním signálem regulované MAP kinasy antagonisté a inhibitory   metabolismus   MeSH
• inhibitory proteinkinas terapeutické užití   MeSH
• lidé MeSH
• nádory farmakoterapie   metabolismus   MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   metabolismus   MeSH
• signální dráha Hippo MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• antitumorózní látky MeSH
• extracelulárním signálem regulované MAP kinasy MeSH
• inhibitory proteinkinas MeSH
• protein-serin-threoninkinasy MeSH

The differential activity of the Hippo-signalling pathway between the outer- and inner-cell populations of the developing preimplantation mouse embryo directs appropriate formation of trophectoderm and inner cell mass (ICM) lineages. Such distinct signalling activity is under control of intracellular polarization, whereby Hippo-signalling is either supressed in polarized outer cells or activated in apolar inner cells. The central role of apical-basolateral polarization to such differential Hippo-signalling regulation prompted us to reinvestigate the role of potential upstream molecular regulators affecting apical-basolateral polarity. This study reports that the chemical inhibition of Rho-associated kinase (Rock) is associated with failure to form morphologically distinct blastocysts, indicative of compromised trophectoderm differentiation, and defects in the localization of both apical and basolateral polarity factors associated with malformation of tight junctions. Moreover, Rock-inhibition mediates mislocalization of the Hippo-signalling activator Angiomotin (Amot), to the basolateral regions of outer cells and is concomitant with aberrant activation of the pathway. The Rock-inhibition phenotype is mediated by Amot, as RNAi-based Amot knockdown totally rescues the normal suppression of Hippo-signalling in outer cells. In conclusion, Rock, via regulating appropriate apical-basolateral polarization in outer cells, regulates the appropriate activity of the Hippo-signalling pathway, by ensuring correct subcellular localization of Amot protein in outer cells.

• Klíčová slova
• Angiomotin, Hippo-signalling, Rho-associated protein kinase (Rock), polarization, preimplantation stage embryo,
• MeSH
• angiomotiny MeSH
• blastocysta metabolismus   MeSH
• embryonální vývoj * MeSH
• kinázy asociované s rho genetika   metabolismus   fyziologie   MeSH
• mezibuněčné signální peptidy a proteiny analýza   metabolismus   MeSH
• mikrofilamentové proteiny analýza   metabolismus   MeSH
• myši MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• signální dráha Hippo MeSH
• signální transdukce MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• Amot protein, mouse MeSH Prohlížeč
• angiomotiny MeSH
• kinázy asociované s rho MeSH
• mezibuněčné signální peptidy a proteiny MeSH
• mikrofilamentové proteiny MeSH
• protein-serin-threoninkinasy MeSH

Binding of the transcriptional co-activator YAP with the transcription factor TEAD stimulates growth of the heart and other organs. YAP overexpression potently stimulates fetal cardiomyocyte (CM) proliferation, but YAP's mitogenic potency declines postnatally. While investigating factors that limit YAP's postnatal mitogenic activity, we found that the CM-enriched TEAD1 binding protein VGLL4 inhibits CM proliferation by inhibiting TEAD1-YAP interaction and by targeting TEAD1 for degradation. Importantly, VGLL4 acetylation at lysine 225 negatively regulated its binding to TEAD1. This developmentally regulated acetylation event critically governs postnatal heart growth, since overexpression of an acetylation-refractory VGLL4 mutant enhanced TEAD1 degradation, limited neonatal CM proliferation, and caused CM necrosis. Our study defines an acetylation-mediated, VGLL4-dependent switch that regulates TEAD stability and YAP-TEAD activity. These insights may improve targeted modulation of TEAD-YAP activity in applications from cardiac regeneration to cancer.

• Klíčová slova
• Hippo-YAP pathway, TEAD1, VGLL4, acetylation, cardiac, cardiomyocyte, degradation, necrosis, proliferation,
• MeSH
• acetylace MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• fosfoproteiny metabolismus   MeSH
• lidé MeSH
• novorozená zvířata MeSH
• potkani Wistar MeSH
• proliferace buněk MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteinové domény MeSH
• proteiny buněčného cyklu MeSH
• sekvence aminokyselin MeSH
• signální dráha Hippo MeSH
• signální proteiny YAP MeSH
• signální transdukce * MeSH
• srdce růst a vývoj   MeSH
• srdeční selhání metabolismus   patologie   MeSH
• stabilita proteinů MeSH
• stárnutí metabolismus   MeSH
• transkripční faktory TEA domény MeSH
• transkripční faktory chemie   metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• DNA vazebné proteiny MeSH
• fosfoproteiny MeSH
• protein-serin-threoninkinasy MeSH
• proteiny buněčného cyklu MeSH
• signální proteiny YAP MeSH
• Tead1 protein, mouse MeSH Prohlížeč
• transkripční faktory TEA domény MeSH
• transkripční faktory MeSH
• VGLL4 protein, mouse MeSH Prohlížeč
• Yap1 protein, mouse MeSH Prohlížeč

In this review, we address aspects of Wnt, R-Spondin (RSPO) and Hippo signalling, in both healthy and transformed intestinal epithelium. In intestinal stem cells (ISCs), the Wnt pathway is essential for intestinal crypt formation and renewal, whereas RSPO-mediated signalling mainly affects ISC numbers. In human colorectal cancer (CRC), aberrant Wnt signalling is the driving mechanism initiating this type of neoplasia. The signalling role of the RSPO-binding transmembrane proteins, the leucine-rich-repeat-containing G-protein-coupled receptors (LGRs), is possibly more pleiotropic and not only limited to the enhancement of Wnt signalling. There is growing evidence for multiple crosstalk between Hippo and Wnt/β-catenin signalling. In the ON state, Hippo signalling results in serine/threonine phosphorylation of Yes-associated protein (YAP1) and tafazzin (TAZ), promoting formation of the β-catenin destruction complex. In contrast, YAP1 or TAZ dephosphorylation (and YAP1 methylation) results in β-catenin destruction complex deactivation and β-catenin nuclear localization. In the Hippo OFF state, YAP1 and TAZ are engaged with the nuclear β-catenin and participate in the β-catenin-dependent transcription program. Interestingly, YAP1/TAZ are dispensable for intestinal homeostasis; however, upon Wnt pathway hyperactivation, the proteins together with TEA domain (TEAD) transcription factors drive the transcriptional program essential for intestinal cell transformation. In addition, in many CRC cells, YAP1 phosphorylation by YES proto-oncogene 1 tyrosine kinase (YES1) leads to the formation of a transcriptional complex that includes YAP1, β-catenin and T-box 5 (TBX5) DNA-binding protein. YAP1/β-catenin/T-box 5-mediated transcription is necessary for CRC cell proliferation and survival. Interestingly, dishevelled (DVL) appears to be an important mediator involved in both Wnt and Hippo (YAP1/TAZ) signalling and some of the DVL functions were assigned to the nuclear DVL pool. Wnt ligands can trigger alternative signalling that directly involves some of the Hippo pathway components such as YAP1, TAZ and TEADs. By upregulating Wnt pathway agonists, the alternative Wnt signalling can inhibit the canonical Wnt pathway activity.

• Klíčová slova
• Hippo pathway, LGR, R-Spondins, Wnt/β-catenin signalling, YAP1/TAZ, colorectal cancer,
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH

Bio-nano interactions have been extensively explored in nanomedicine to develop selective delivery strategies and reduce systemic toxicity. To enhance the delivery of nanocarriers to cancer cells and improve the therapeutic efficiency, different nanomaterials have been developed. However, the limited clinical translation of nanoparticle-based therapies, largely due to issues associated with poor targeting, requires a deeper understanding of the biological phenomena underlying cell-nanoparticle interactions. In this context, we investigate the molecular and cellular mechanobiology parameters that control such interactions. We demonstrate that the pharmacological inhibition or the genetic ablation of the key mechanosensitive component of the Hippo pathway, i.e., yes-associated protein, enhances nanoparticle internalization by 1.5-fold. Importantly, this phenomenon occurs independently of nanoparticle properties, such as size, or cell properties such as surface area and stiffness. Our study reveals that the internalization of nanoparticles in target cells can be controlled by modulating cell mechanosensing pathways, potentially enhancing nanotherapy specificity.

• Klíčová slova
• bio−nano interactions, mechanobiology, mechanotransduction, nanoparticles,
• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• buněčný převod mechanických signálů účinky léků   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nanočástice * chemie   MeSH
• nanomedicína MeSH
• signální dráha Hippo MeSH
• signální proteiny YAP MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• signální proteiny YAP MeSH
• YAP1 protein, human MeSH Prohlížeč

Cytochrome P450 family 1 (CYP1) enzymes contribute both to metabolism of xenobiotics and to the control of endogenous levels of ligands of the aryl hydrocarbon receptor (AhR). Their activities, similar to other CYPs, can be altered in tumor tissues. Here, we examined a possible role of proliferative/survival pathways signaling, which is often deregulated in tumor cells, and possible links with p300 histone acetyltransferase (a transcriptional co-activator) in the control of CYP1 expression, focusing particularly on CYP1A1. Using cell models derived from human liver, we observed that the induction of CYP1A1 expression, as well as other CYP1 enzymes, was reduced in exponentially growing cells, as compared with their non-dividing counterparts. The siRNA-mediated inhibition of proliferation/pro-survival signaling pathway effectors (such as β-catenin and/or Hippo pathway effectors YAP/TAZ) increased the AhR ligand-induced CYP1A1 mRNA levels in liver HepaRG cells, and/or in colon carcinoma HCT-116 cells. The activation of proliferative Wnt/β-catenin signaling in HCT-116 cells reduced both the induction of CYP1 enzymes and the binding of p300 to the promoter of CYP1A1 or CYP1B1 genes. These results seem to indicate that aberrant proliferative signaling in tumor cells could suppress induction of CYP1A1 (or other CYP1 enzymes) via competition for p300 binding. This mechanism could be involved in modulation of the metabolism of both endogenous and exogenous substrates of CYP1A1 (and other CYP1 enzymes), with possible further consequences for alterations of the AhR signaling in tumor cells, or additional functional roles of CYP1 enzymes.

• Klíčová slova
• AhR, CYP1 enzymes, Cancer cells, Cell proliferation, p300, β-Catenin signaling,
• MeSH
• cytochrom P-450 CYP1A1 biosyntéza   genetika   MeSH
• enzymová indukce fyziologie   MeSH
• HCT116 buňky MeSH
• játra patologie   MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• nádory tračníku genetika   patologie   MeSH
• proliferace buněk fyziologie   MeSH
• protein p300 asociovaný s E1A metabolismus   MeSH
• regulace genové exprese u nádorů MeSH
• signální dráha Hippo fyziologie   MeSH
• signální dráha Wnt fyziologie   MeSH
• signální transdukce fyziologie   MeSH
• viabilita buněk fyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• CYP1A1 protein, human MeSH Prohlížeč
• cytochrom P-450 CYP1A1 MeSH
• EP300 protein, human MeSH Prohlížeč
• protein p300 asociovaný s E1A MeSH

Colorectal cancer (CRC) is a heterogeneous disease that includes both hereditary and sporadic types of tumors. Tumor initiation and growth is driven by mutational or epigenetic changes that alter the function or expression of multiple genes. The genes predominantly encode components of various intracellular signaling cascades. In this review, we present mouse intestinal cancer models that include alterations in the Wnt, Hippo, p53, epidermal growth factor (EGF), and transforming growth factor β (TGFβ) pathways; models of impaired DNA mismatch repair and chemically induced tumorigenesis are included. Based on their molecular biology characteristics and mutational and epigenetic status, human colorectal carcinomas were divided into four so-called consensus molecular subtype (CMS) groups. It was shown subsequently that the CMS classification system could be applied to various cell lines derived from intestinal tumors and tumor-derived organoids. Although the CMS system facilitates characterization of human CRC, individual mouse models were not assigned to some of the CMS groups. Thus, we also indicate the possible assignment of described animal models to the CMS group. This might be helpful for selection of a suitable mouse strain to study a particular type of CRC.

• Klíčová slova
• carcinoma, consensus molecular subtypes, intestine, oncogenes, signaling cascades, tumor suppressors, tumorigenesis,
• MeSH
• epidermální růstový faktor genetika   MeSH
• geny p53 genetika   MeSH
• karcinogeneze genetika   MeSH
• kolorektální nádory klasifikace   metabolismus   patofyziologie   MeSH
• lidé MeSH
• modely nemocí na zvířatech MeSH
• myši MeSH
• nádorová transformace buněk genetika   MeSH
• nádory tračníku genetika   MeSH
• oprava chybného párování bází DNA genetika   MeSH
• protein-serin-threoninkinasy genetika   MeSH
• regulace genové exprese u nádorů genetika   MeSH
• signální dráha Hippo MeSH
• signální dráha Wnt genetika   MeSH
• transformující růstový faktor beta genetika   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• epidermální růstový faktor MeSH
• protein-serin-threoninkinasy MeSH
• transformující růstový faktor beta MeSH

The proapoptotic protein Noxa, a member of the BH3-only Bcl-2 protein family, can effectively induce apoptosis in cancer cells, although the relevant regulatory pathways have been obscure. Previous studies of the cytotoxic effects of α-tocopheryl succinate (α-TOS) on cancer cells identified a mechanism whereby α-TOS caused apoptosis requiring the Noxa-Bak axis. In the present study, ab initio analysis revealed a conserved FoxO-binding site (DBE; DAF-16 binding element) in the NOXA promoter, and specific affinity of FoxO proteins to this DBE was confirmed by fluorescence anisotropy. FoxO1 and FoxO3a proteins accumulated in the nucleus of α-TOS-treated cells, and the drug-induced specific FoxO1 association with the NOXA promoter and its activation were validated by chromatin immunoprecipitation. Using siRNA knockdown, a specific role for the FoxO1 protein in activating NOXA transcription in cancer cells was identified. Furthermore, the proapoptotic kinase Hippo/Mst1 was found to be strongly activated by α-TOS, and inhibiting Hippo/Mst1 by specific siRNA prevented phosphorylation of FoxO1 and its nuclear translocation, thereby reducing levels of NOXA transcription and apoptosis in cancer cells exposed to α-TOS. Thus, we have demonstrated that anticancer drugs, exemplified by α-TOS, induce apoptosis by a mechanism involving the Hippo/Mst1-FoxO1-Noxa pathway. We propose that activation of this pathway provides a new paradigm for developing targeted cancer treatments.

• MeSH
• alfa-tokoferol farmakologie   MeSH
• apoptóza fyziologie   MeSH
• forkhead box protein O1 MeSH
• forkhead transkripční faktory genetika   metabolismus   MeSH
• genetická transkripce MeSH
• intracelulární signální peptidy a proteiny MeSH
• Jurkat buňky MeSH
• lidé MeSH
• lymfom T-buněčný genetika   metabolismus   patologie   terapie   MeSH
• malá interferující RNA aplikace a dávkování   genetika   MeSH
• nádorové buněčné linie MeSH
• nádory plic genetika   metabolismus   patologie   terapie   MeSH
• nemalobuněčný karcinom plic genetika   metabolismus   patologie   terapie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• promotorové oblasti (genetika) MeSH
• protein-serin-threoninkinasy antagonisté a inhibitory   genetika   metabolismus   MeSH
• protoonkogenní proteiny c-bcl-2 biosyntéza   genetika   metabolismus   MeSH
• signální transdukce MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• alfa-tokoferol MeSH
• forkhead box protein O1 MeSH
• forkhead transkripční faktory MeSH
• FOXO1 protein, human MeSH Prohlížeč
• intracelulární signální peptidy a proteiny MeSH
• malá interferující RNA MeSH
• PMAIP1 protein, human MeSH Prohlížeč
• protein-serin-threoninkinasy MeSH
• protoonkogenní proteiny c-bcl-2 MeSH
• STK4 protein, human MeSH Prohlížeč

Cells have developed a unique set of molecular mechanisms that allows them to probe mechanical properties of the surrounding environment. These systems are based on deformable primary mechanosensors coupled to tension transmitting proteins and enzymes generating biochemical signals. This modular setup enables to transform a mechanical load into more versatile biochemical information. Src kinase appears to be one of the central components of the mechanotransduction network mediating force-induced signalling across multiple cellular contexts. In tight cooperation with primary sensors and the cytoskeleton, Src functions as an effector molecule necessary for transformation of mechanical stimuli into biochemical outputs executing cellular response and adaptation to mechanical cues.

• Klíčová slova
• Cytoskeleton, Integrins, Mechanosensing, Src, YAP, p130Cas,
• MeSH
• adaptorové proteiny signální transdukční genetika   metabolismus   MeSH
• buněčný převod mechanických signálů genetika   MeSH
• cytoskelet metabolismus   patologie   ultrastruktura   MeSH
• extracelulární matrix metabolismus   patologie   ultrastruktura   MeSH
• integriny genetika   metabolismus   MeSH
• lidé MeSH
• mechanický stres MeSH
• nádory genetika   metabolismus   patologie   MeSH
• protein-serin-threoninkinasy genetika   metabolismus   MeSH
• regulace genové exprese MeSH
• signální dráha Hippo MeSH
• signální proteiny YAP MeSH
• skupina kinas odvozených od src-genu genetika   metabolismus   MeSH
• substrátový protein asociovaný s Crk genetika   metabolismus   MeSH
• transkripční faktory genetika   metabolismus   MeSH
• tyrosinfosfatasy receptorového typu, třída 4 genetika   metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• BCAR1 protein, human MeSH Prohlížeč
• integriny MeSH
• protein-serin-threoninkinasy MeSH
• PTPRA protein, human MeSH Prohlížeč
• signální proteiny YAP MeSH
• skupina kinas odvozených od src-genu MeSH
• substrátový protein asociovaný s Crk MeSH
• transkripční faktory MeSH
• tyrosinfosfatasy receptorového typu, třída 4 MeSH
• YAP1 protein, human MeSH Prohlížeč

Phosphorylation-dependent YAP translocation is a well-known intracellular mechanism of the Hippo pathway; however, the molecular effectors governing YAP cytoplasmic translocation remains undefined. Recent findings indicate that oncogenic YAP paradoxically suppresses Wnt activity. Here, we show that Wnt scaffolding protein Dishevelled (DVL) is responsible for cytosolic translocation of phosphorylated YAP. Mutational inactivation of the nuclear export signal embedded in DVL leads to nuclear YAP retention, with an increase in TEAD transcriptional activity. DVL is also required for YAP subcellular localization induced by E-cadherin, α-catenin, or AMPK activation. Importantly, the nuclear-cytoplasmic trafficking is dependent on the p53-Lats2 or LKB1-AMPK tumor suppressor axes, which determine YAP phosphorylation status. In vivo and clinical data support that the loss of p53 or LKB1 relieves DVL-linked reciprocal inhibition between the Wnt and nuclear YAP activity. Our observations provide mechanistic insights into controlled proliferation coupled with epithelial polarity during development and human cancer.

• MeSH
• adaptorové proteiny signální transdukční metabolismus   MeSH
• aktivní transport - buněčné jádro * MeSH
• alfa-katenin metabolismus   MeSH
• buněčné jádro metabolismus   MeSH
• buňky A549 MeSH
• cytoplazma metabolismus   MeSH
• fosfoproteiny metabolismus   MeSH
• fosforylace MeSH
• HCT116 buňky MeSH
• HEK293 buňky MeSH
• kadheriny metabolismus   MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• lidé MeSH
• MFC-7 buňky MeSH
• mutace MeSH
• mutační analýza DNA MeSH
• myši nahé MeSH
• myši MeSH
• nádorový supresorový protein p53 metabolismus   MeSH
• protein dishevelled metabolismus   MeSH
• protein Wnt1 metabolismus   MeSH
• protein-serin-threoninkinasy metabolismus   MeSH
• proteinkinasy aktivované AMP metabolismus   MeSH
• proteiny buněčného cyklu MeSH
• proteiny Wnt metabolismus   MeSH
• signální dráha Hippo MeSH
• signální proteiny YAP MeSH
• transkripční faktory MeSH
• transport proteinů MeSH
• tumor supresorové geny * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adaptorové proteiny signální transdukční MeSH
• alfa-katenin MeSH
• DVL1 protein, human MeSH Prohlížeč
• fosfoproteiny MeSH
• kadheriny MeSH
• kinasy AMP aktivovaných proteinkinas MeSH
• nádorový supresorový protein p53 MeSH
• protein dishevelled MeSH
• protein Wnt1 MeSH
• protein-serin-threoninkinasy MeSH
• proteinkinasy aktivované AMP MeSH
• proteiny buněčného cyklu MeSH
• proteiny Wnt MeSH
• signální proteiny YAP MeSH
• STK11 protein, human MeSH Prohlížeč
• TP53 protein, human MeSH Prohlížeč
• transkripční faktory MeSH
• WNT1 protein, human MeSH Prohlížeč
• YAP1 protein, human MeSH Prohlížeč
• Yap1 protein, mouse MeSH Prohlížeč