TY - GEN AU - Kurilla, Anita AU - László, Loretta AU - Takács, Tamás AU - Tilajka, Álmos AU - Laura, Lukacs AU - Julianna, Novak AU - Pancsa, Rita AU - Buday, László AU - Vas, Virág TI - The regulatory role of the CD2AP/TKS4 interaction in EMT and its potential as a biomarker for colon cancer PY - 2023 UR - https://m2.mtmt.hu/api/publication/34768197 ID - 34768197 LA - English DB - MTMT ER - TY - JOUR AU - Kurilla, Anita AU - László, Loretta AU - Takács, Tamás AU - Tilajka, Álmos AU - Lukács, L. AU - Novák, J. AU - Pancsa, Rita AU - Buday, László AU - Vas, Virág TI - Studying the Association of TKS4 and CD2AP Scaffold Proteins and Their Implications in the Partial Epithelial–Mesenchymal Transition (EMT) Process JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 24 PY - 2023 IS - 20 PG - 17 SN - 1661-6596 DO - 10.3390/ijms242015136 UR - https://m2.mtmt.hu/api/publication/34266900 ID - 34266900 LA - English DB - MTMT ER - TY - JOUR AU - László, Loretta AU - Maczelka, Hédi AU - Takács, Tamás AU - Kurilla, Anita AU - Tilajka, Álmos AU - Buday, László AU - Vas, Virág AU - Apáti, Ágota TI - A Novel Cell-Based Model for a Rare Disease: The Tks4-KO Human Embryonic Stem Cell Line as a Frank-Ter Haar Syndrome Model System JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 23 PY - 2022 IS - 15 PG - 15 SN - 1661-6596 DO - 10.3390/ijms23158803 UR - https://m2.mtmt.hu/api/publication/33063952 ID - 33063952 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary National Laboratory for Drug Research and Development, Budapest, 1117, Hungary Doctoral School of Biology, Institute of Biology, ELTE Eötvös Loránd University, Budapest, 1117, Hungary Basic and Translational Medicine Doctoral School, Semmelweis University, Budapest, 1085, Hungary Export Date: 9 December 2022 Correspondence Address: Vas, V.; Institute of Enzymology, Hungary; email: vas.virag@ttk.hu Correspondence Address: Apáti, Á.; Institute of Enzymology, Hungary; email: apati.agota@ttk.hu AB - Tyrosine kinase substrate with four SH3 domains (Tks4) scaffold protein plays roles in cell migration and podosome formation and regulates systemic mechanisms such as adult bone homeostasis and adipogenesis. Mutations in the Tks4 gene (SH3PXD2b) cause a rare developmental disorder called Frank-Ter Haar syndrome (FTHS), which leads to heart abnormalities, bone tissue defects, and reduced adiposity. We aimed to produce a human stem cell-based in vitro FTHS model system to study the effects of the loss of the Tks4 protein in different cell lineages and the accompanying effects on the cell signalome. To this end, we used CRISPR/Cas9 (clustered, regularly interspaced, short palindromic repeats (CRISPR)/CRISPR associated (Cas9)) to knock out the SH3PXD2b gene in the HUES9 human embryonic stem cell line (hESC), and we obtained stable homo- and heterozygous knock out clones for use in studying the potential regulatory roles of Tks4 protein in embryonic stem cell biology. Based on pluripotency marker measurements and spontaneous differentiation capacity assays, we concluded that the newly generated Tks4-KO HUES9 cells retained their embryonic stem cell characteristics. We propose that the Tks4-KO HUES9 cells could serve as a tool for further cell differentiation studies to investigate the involvement of Tks4 in the complex disorder FTHS. Moreover, we successfully differentiated all of the clones into mesenchymal stem cells (MSCs). The derived MSC cultures showed mesenchymal morphology and expressed MSC markers, although the expression levels of mesodermal and osteogenic marker genes were reduced, and several EMT (epithelial mesenchymal transition)-related features were altered in the Tks4-KO MSCs. Our results suggest that the loss of Tks4 leads to FTHS by altering cell lineage differentiation and cell maturation processes, rather than by regulating embryonic stem cell potential. LA - English DB - MTMT ER - TY - JOUR AU - Menyhart, Otilia AU - Vas, Virág AU - Győrffy, Balázs AU - Buday, László TI - A személyre szabott terápia legújabb lehetőségei a molekuláris onkológiában JF - SCIENTIA ET SECURITAS J2 - SCI SEC VL - 2 PY - 2021 IS - 2 SP - 191 EP - 199 PG - 9 SN - 2732-2688 DO - 10.1556/112.2021.00035 UR - https://m2.mtmt.hu/api/publication/32369276 ID - 32369276 AB - A molekuláris onkológia térnyerésével számos új lehetőség érhető el a daganatos betegek hatékonyabb kezelésére. Ilyen a klinikai vizsgálatokban alkalmazott, a valóban személyre szabott kezelést elősegítő génpanelelemzés, illetve a célzott kezelés szövettípustól független alkalmazása. A személyre szabott terápiák jelentős hányada valamelyik kinázt gátolja. Az összefoglalónkban bemutatjuk a RAS jelátviteli út sejten belüli komplex szabályozását, valamint ismertetjük az útvonal további farmakológiai szempontból kiaknázható célpontjait nemzetközi és saját eredményeink alapján. A kinázokat érintő gyakori mutációk ellenére számos daganattípusban nem áll rendelkezésre személyre szabott terápia. A hagyományos terápiával nem kezelhető agydaganatok példáján keresztül bemutatjuk a tirozin-kinázok várható jövőbeli terápiás jelentőségét. LA - Hungarian DB - MTMT ER - TY - JOUR AU - Merő, Balázs László AU - Koprivanacz, Kitti AU - Cserkaszky, A. AU - Radnai, L. AU - Vas, Virág AU - Kudlik, Gyöngyi AU - Gógl, Gergő AU - Sok, Péter Dániel AU - Póti, Ádám Levente AU - Szeder, Bálint AU - Nyitray, László AU - Reményi, Attila AU - Geiszt, Miklós AU - Buday, László TI - Characterization of the intramolecular interactions and regulatory mechanisms of the scaffold protein tks4 JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 22 PY - 2021 IS - 15 PG - 19 SN - 1661-6596 DO - 10.3390/ijms22158103 UR - https://m2.mtmt.hu/api/publication/32127826 ID - 32127826 N1 - Research Centre for Natural Sciences, Institute of Enzymology, Budapest, 1117, Hungary Department of Biochemistry, Eötvös Loránd University, Budapest, 1117, Hungary Research Centre for Natural Sciences, Institute of Organic Chemistry, Budapest, 1117, Hungary Department of Physiology, Semmelweis University, Budapest, 1094, Hungary Department of Molecular Biology, Semmelweis University Medical School, Budapest, 1094, Hungary Cited By :1 Export Date: 9 December 2022 Correspondence Address: Buday, L.; Department of Biochemistry, Hungary; email: buday.laszlo@ttk.hu AB - The scaffold protein Tks4 is a member of the p47phox‐related organizer superfamily. It plays a key role in cell motility by being essential for the formation of podosomes and invadopodia. In addition, Tks4 is involved in the epidermal growth factor (EGF) signaling pathway, in which EGF induces the translocation of Tks4 from the cytoplasm to the plasma membrane. The evolutionarily‐related protein p47phox and Tks4 share many similarities in their N‐terminal region: a phosphoinositide‐binding PX domain is followed by two SH3 domains (so called “tandem SH3”) and a proline‐rich region (PRR). In p47phox, the PRR is followed by a relatively short, disordered C‐terminal tail region containing multiple phosphorylation sites. These play a key role in the regulation of the protein. In Tks4, the PRR is followed by a third and a fourth SH3 domain connected by a long (~420 residues) unstructured region. In p47phox, the tandem SH3 domain binds the PRR while the first SH3 domain interacts with the PX domain, thereby preventing its binding to the membrane. Based on the conserved structural features of p47phox and Tks4 and the fact that an intramolecular interaction between the third SH3 and the PX domains of Tks4 has already been reported, we hypothesized that Tks4 is similarly regulated by autoinhibition. In this study, we showed, via fluorescence‐based titrations, MST, ITC, and SAXS measurements, that the tandem SH3 domain of Tks4 binds the PRR and that the PX domain interacts with the third SH3 domain. We also investigated a phosphomimicking Thr‐to‐Glu point mutation in the PRR as a possible regulator of intramolecular interactions. Phosphatidylinositol‐3‐phosphate (PtdIns(3)P) was identified as the main binding partner of the PX domain via lipid‐binding assays. In truncated Tks4 fragments, the presence of the tandem SH3, together with the PRR, reduced PtdIns(3)P binding, while the presence of the third SH3 domain led to complete inhibition. © 2021 by the authors. Licensee MDPI, Basel, Switzerland. LA - English DB - MTMT ER - TY - JOUR AU - László, Loretta AU - Kurilla, Anita AU - Takács, Tamás AU - Kudlik, Gyöngyi AU - Koprivanacz, Kitti AU - Buday, László AU - Vas, Virág TI - Recent updates on the significance of KRAS mutations in colorectal cancer biology JF - CELLS J2 - CELLS-BASEL VL - 10 PY - 2021 IS - 3 PG - 20 SN - 2073-4409 DO - 10.3390/cells10030667 UR - https://m2.mtmt.hu/api/publication/31909245 ID - 31909245 N1 - Funding Agency and Grant Number: National Research, Development and Innovation Fund of Hungary [K 124045, FIEK_16-1-2016-0005, HunProtEx 2018-1.2.1-NKP-2018-00005]; MedinProt Program of the Hungarian Academy of Sciences Funding text: This work was supported by grants from the National Research, Development and Innovation Fund of Hungary (K 124045, FIEK_16-1-2016-0005, HunProtEx 2018-1.2.1-NKP-2018-00005, L.B.) and the MedinProt Program of the Hungarian Academy of Sciences (L.B.). LA - English DB - MTMT ER - TY - JOUR AU - Kudlik, Gyöngyi AU - Takács, Tamás AU - Radnai, L. AU - Kurilla, Anita AU - Szeder, Bálint AU - Koprivanacz, Kitti AU - Merő, Balázs László AU - Buday, László AU - Vas, Virág TI - Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 21 PY - 2020 IS - 21 PG - 28 SN - 1661-6596 DO - 10.3390/ijms21218117 UR - https://m2.mtmt.hu/api/publication/31662756 ID - 31662756 N1 - Institute of Enzymology, Research Centre for Natural SciencesBudapest 1117, Hungary Department of Molecular Medicine, Scripps Research Institute, Jupiter, FL 33458, United States Department of Medical Chemistry, Semmelweis University Medical SchoolBudapest 1085, Hungary Export Date: 16 November 2020 AB - Scaffold proteins are typically thought of as multi-domain "bridging molecules." They serve as crucial regulators of key signaling events by simultaneously binding multiple participants involved in specific signaling pathways. In the case of epidermal growth factor (EGF)-epidermal growth factor receptor (EGFR) binding, the activated EGFR contacts cytosolic SRC tyrosine-kinase, which then becomes activated. This process leads to the phosphorylation of SRC-substrates, including the tyrosine kinase substrates (TKS) scaffold proteins. The TKS proteins serve as a platform for the recruitment of key players in EGFR signal transduction, promoting cell spreading and migration. The TKS4 and the TKS5 scaffold proteins are tyrosine kinase substrates with four or five SH3 domains, respectively. Their structural features allow them to recruit and bind a variety of signaling proteins and to anchor them to the cytoplasmic surface of the cell membrane. Until recently, TKS4 and TKS5 had been recognized for their involvement in cellular motility, reactive oxygen species-dependent processes, and embryonic development, among others. However, a number of novel functions have been discovered for these molecules in recent years. In this review, we attempt to cover the diverse nature of the TKS molecules by discussing their structure, regulation by SRC kinase, relevant signaling pathways, and interaction partners, as well as their involvement in cellular processes, including migration, invasion, differentiation, and adipose tissue and bone homeostasis. We also describe related pathologies and the established mouse models. LA - English DB - MTMT ER - TY - JOUR AU - Buday, László AU - Vas, Virág TI - Novel regulation of Ras proteins by direct tyrosine phosphorylation and dephosphorylation JF - CANCER AND METASTASIS REVIEWS J2 - CANCER METAST REV VL - 39 PY - 2020 IS - 4 SP - 1067 EP - 1073 PG - 7 SN - 0167-7659 DO - 10.1007/s10555-020-09918-2 UR - https://m2.mtmt.hu/api/publication/31607092 ID - 31607092 AB - Somatic mutations in the RAS genes are frequent in human tumors, especially in pancreatic, colorectal, and non-small-cell lung cancers. Such mutations generally decrease the ability of Ras to hydrolyze GTP, maintaining the protein in a constitutively active GTP-bound form that drives uncontrolled cell proliferation. Efforts to develop drugs that target Ras oncoproteins have been unsuccessful. Recent emerging data suggest that Ras regulation is more complex than the scientific community has believed for decades. In this review, we summarize advances in the "textbook" view of Ras activation. We also discuss a novel type of Ras regulation that involves direct phosphorylation and dephosphorylation of Ras tyrosine residues. The discovery that pharmacological inhibition of the tyrosine phosphoprotein phosphatase SHP2 maintains mutant Ras in an inactive state suggests that SHP2 could be a novel drug target for the treatment of Ras-driven human cancers. LA - English DB - MTMT ER - TY - JOUR AU - Takács, Tamás AU - Kudlik, Gyöngyi AU - Kurilla, Anita AU - Szeder, Bálint AU - Buday, László AU - Vas, Virág TI - The effects of mutant Ras proteins on the cell signalome JF - CANCER AND METASTASIS REVIEWS J2 - CANCER METAST REV VL - 39 PY - 2020 IS - 4 SP - 1051 EP - 1065 PG - 15 SN - 0167-7659 DO - 10.1007/s10555-020-09912-8 UR - https://m2.mtmt.hu/api/publication/31400188 ID - 31400188 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Medical Chemistry, Semmelweis University Medical School, Budapest, Hungary Export Date: 11 August 2020 CODEN: CMRED Correspondence Address: Vas, V.; Institute of Enzymology, Research Centre for Natural SciencesHungary; email: vas.virag@ttk.hu Funding details: Magyar Tudományos Akadémia, MTA Funding details: K 124045, HunProEx 2018-1.2.1-NKP-2018-00005, ANN 118119, FIEK_16-1-2016-0005 Funding text 1: Open access funding provided by ELKH Research Centre for Natural Sciences. This work was supported by the grants from the National Research, Development and Innovation Fund of Hungary (K 124045, FIEK_16-1-2016-0005, HunProEx 2018-1.2.1-NKP-2018-00005, L.B.) (ANN 118119, A.C) and the MedinProt Program of the Hungarian Academy of Sciences (L.B.). The work of V.V. was supported by a János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Institute of Enzymology, Research Centre for Natural Sciences, Budapest, Hungary Department of Medical Chemistry, Semmelweis University Medical School, Budapest, Hungary Export Date: 4 January 2021 CODEN: CMRED Correspondence Address: Vas, V.; Institute of Enzymology, Research Centre for Natural SciencesHungary; email: vas.virag@ttk.hu Funding details: Magyar Tudományos Akadémia, MTA Funding details: K 124045, HunProEx 2018-1.2.1-NKP-2018-00005, ANN 118119, FIEK_16-1-2016-0005 Funding text 1: Open access funding provided by ELKH Research Centre for Natural Sciences. This work was supported by the grants from the National Research, Development and Innovation Fund of Hungary (K 124045, FIEK_16-1-2016-0005, HunProEx 2018-1.2.1-NKP-2018-00005, L.B.) (ANN 118119, A.C) and the MedinProt Program of the Hungarian Academy of Sciences (L.B.). The work of V.V. was supported by a János Bolyai Research Scholarship of the Hungarian Academy of Sciences. Acknowledgments AB - The genetic alterations in cancer cells are tightly linked to signaling pathway dysregulation. Ras is a key molecule that controls several tumorigenesis-related processes, and mutations in RAS genes often lead to unbiased intensification of signaling networks that fuel cancer progression. In this article, we review recent studies that describe mutant Ras-regulated signaling routes and their cross-talk. In addition to the two main Ras-driven signaling pathways, i.e., the RAF/MEK/ERK and PI3K/AKT/mTOR pathways, we have also collected emerging data showing the importance of Ras in other signaling pathways, including the RAC/PAK, RalGDS/Ral, and PKC/PLC signaling pathways. Moreover, microRNA-regulated Ras-associated signaling pathways are also discussed to highlight the importance of Ras regulation in cancer. Finally, emerging data show that the signal alterations in specific cell types, such as cancer stem cells, could promote cancer development. Therefore, we also cover the up-to-date findings related to Ras-regulated signal transduction in cancer stem cells. © 2020, The Author(s). LA - English DB - MTMT ER - TY - JOUR AU - Bencsik, Norbert AU - Pusztai, Szilvia AU - Borbély, Sándor AU - Fekete, Anna AU - Dülk, Metta AU - Kis, Viktor AU - Pesti, Szabolcs AU - Vas, Virág AU - Szűcs, Attila AU - Buday, László AU - Schlett, Katalin TI - Dendritic spine morphology and memory formation depend on postsynaptic Caskin proteins JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 9 PY - 2019 IS - 1 PG - 16 SN - 2045-2322 DO - 10.1038/s41598-019-53317-9 UR - https://m2.mtmt.hu/api/publication/30920816 ID - 30920816 N1 - Funding Agency and Grant Number: "Momentum" grant; New National Excellence Program of the Ministry of Human Capacities; Gedeon Richter Centenarium Foundation; National Brain Research Programs [KTIA_NAP_13-2-2014-0018, 2017-1.2.1-NKP-2017-00002]; NRDIONational Research, Development & Innovation Office (NRDIO) - Hungary [VEKOP-2.3.3-15-2016-00007]; Janos Bolyai Research Scolarship of HAS Funding text: This work was supported by the "Momentum" grant to L.B., by through the New National Excellence Program of the Ministry of Human Capacities to N.B., by the Gedeon Richter Centenarium Foundation to N.B. and by the National Brain Research Programs (KTIA_NAP_13-2-2014-0018 and 2017-1.2.1-NKP-2017-00002) to KS as well as the VEKOP-2.3.3-15-2016-00007 grant from NRDIO. V.V. and S.B. was supported by Janos Bolyai Research Scolarship of HAS. LA - English DB - MTMT ER -