@article{MTMT:32127826,
	title = {Characterization of the intramolecular interactions and regulatory mechanisms of the scaffold protein tks4},
	url = {https://m2.mtmt.hu/api/publication/32127826},
	author = {Merő, Balázs László and Koprivanacz, Kitti and Cserkaszky, A. and Radnai, L. and Vas, Virág and Kudlik, Gyöngyi and Gógl, Gergő and Sok, Péter Dániel and Póti, Ádám Levente and Szeder, Bálint and Nyitray, László and Reményi, Attila and Geiszt, Miklós and Buday, László},
	doi = {10.3390/ijms22158103},
	journal-iso = {INT J MOL SCI},
	journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
	volume = {22},
	unique-id = {32127826},
	issn = {1661-6596},
	abstract = {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.},
	keywords = {SH3 domain; PX DOMAIN; SAXS; ITC; Tks5; Tks4; scaffold proteins; Lipid binding; MST; PtdIns(3)P; p47; Autoinhibited conformation; Tandem SH3},
	year = {2021},
	eissn = {1422-0067},
	orcid-numbers = {Nyitray, László/0000-0003-4717-5994; Buday, László/0000-0003-3518-5757}
}

@article{MTMT:31909245,
	title = {Recent updates on the significance of KRAS mutations in colorectal cancer biology},
	url = {https://m2.mtmt.hu/api/publication/31909245},
	author = {László, Loretta and Kurilla, Anita and Takács, Tamás and Kudlik, Gyöngyi and Koprivanacz, Kitti and Buday, László and Vas, Virág},
	doi = {10.3390/cells10030667},
	journal-iso = {CELLS-BASEL},
	journal = {CELLS},
	volume = {10},
	unique-id = {31909245},
	year = {2021},
	eissn = {2073-4409},
	orcid-numbers = {László, Loretta/0000-0003-0367-4900; Buday, László/0000-0003-3518-5757}
}

@article{MTMT:31662756,
	title = {Advances in Understanding TKS4 and TKS5: Molecular Scaffolds Regulating Cellular Processes from Podosome and Invadopodium Formation to Differentiation and Tissue Homeostasis},
	url = {https://m2.mtmt.hu/api/publication/31662756},
	author = {Kudlik, Gyöngyi and Takács, Tamás and Radnai, L. and Kurilla, Anita and Szeder, Bálint and Koprivanacz, Kitti and Merő, Balázs László and Buday, László and Vas, Virág},
	doi = {10.3390/ijms21218117},
	journal-iso = {INT J MOL SCI},
	journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
	volume = {21},
	unique-id = {31662756},
	issn = {1661-6596},
	abstract = {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.},
	keywords = {INVASION; Adipose Tissue; Mesenchymal Stem Cells; scaffold protein; EPITHELIAL-MESENCHYMAL TRANSITION; Tks5; Tks4; bone homeostasis; tyrosine kinase substrates},
	year = {2020},
	eissn = {1422-0067},
	orcid-numbers = {Buday, László/0000-0003-3518-5757}
}

@article{MTMT:31400188,
	title = {The effects of mutant Ras proteins on the cell signalome},
	url = {https://m2.mtmt.hu/api/publication/31400188},
	author = {Takács, Tamás and Kudlik, Gyöngyi and Kurilla, Anita and Szeder, Bálint and Buday, László and Vas, Virág},
	doi = {10.1007/s10555-020-09912-8},
	journal-iso = {CANCER METAST REV},
	journal = {CANCER AND METASTASIS REVIEWS},
	volume = {39},
	unique-id = {31400188},
	issn = {0167-7659},
	abstract = {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).},
	keywords = {PHOSPHORYLATION; signal transduction; Tumorigenesis; Mutant Ras protein},
	year = {2020},
	eissn = {1573-7233},
	pages = {1051-1065},
	orcid-numbers = {Buday, László/0000-0003-3518-5757}
}

@article{MTMT:31196937,
	title = {Establishment and Characterization of a Brca1−/−, p53−/− Mouse Mammary Tumor Cell Line},
	url = {https://m2.mtmt.hu/api/publication/31196937},
	author = {Hámori, Lilla and Kudlik, Gyöngyi and Szebényi, Kornélia and Kucsma, Nóra and Szeder, Bálint and Póti, Ádám and Uher, Ferenc and Várady, György and Szüts, Dávid and Tóvári, József and Füredi, András and Szakács, Gergely},
	doi = {10.3390/ijms21041185},
	journal-iso = {INT J MOL SCI},
	journal = {INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES},
	volume = {21},
	unique-id = {31196937},
	issn = {1661-6596},
	year = {2020},
	eissn = {1422-0067},
	orcid-numbers = {Hámori, Lilla/0000-0002-8962-0040; Szebényi, Kornélia/0000-0003-1558-8372; Várady, György/0000-0003-2012-9680; Tóvári, József/0000-0002-5543-3204; Füredi, András/0000-0002-7883-9901}
}

@article{MTMT:30910673,
	title = {Absence of the Tks4 Scaffold Protein Induces Epithelial-Mesenchymal Transition-Like Changes in Human Colon Cancer Cells},
	url = {https://m2.mtmt.hu/api/publication/30910673},
	author = {Szeder, Bálint and Tárnoki-Zách, Júlia and Lakatos, Dóra and Vas, Virág and Kudlik, Gyöngyi and Merő, Balázs László and Koprivanacz, Kitti and Bányai, László and Hámori, Lilla and Róna, Gergely and Czirók, András and Füredi, András and Buday, László},
	doi = {10.3390/cells8111343},
	journal-iso = {CELLS-BASEL},
	journal = {CELLS},
	volume = {8},
	unique-id = {30910673},
	abstract = {Epithelial to mesenchymal transition (EMT) is a multipurpose process involved in wound healing, development, and certain pathological processes, such as metastasis formation. The Tks4 scaffold protein has been implicated in cancer progression; however, its role in oncogenesis is not well defined. In this study, the function of Tks4 was investigated in HCT116 colon cancer cells by knocking the protein out using the CRISPR/Cas9 system. Surprisingly, the absence of Tks4 induced significant changes in cell morphology, motility, adhesion and expression, and localization of E-cadherin, which are all considered as hallmarks of EMT. In agreement with these findings, the marked appearance of fibronectin, a marker of the mesenchymal phenotype, was also observed in Tks4-KO cells. Analysis of the expression of well-known EMT transcription factors revealed that Snail2 was strongly overexpressed in cells lacking Tks4. Tks4-KO cells showed increased motility and decreased cell-cell attachment. Collagen matrix invasion assays demonstrated the abundance of invasive solitary cells. Finally, the reintroduction of Tks4 protein in the Tks4-KO cells restored the expression levels of relevant key transcription factors, suggesting that the Tks4 scaffold protein has a specific and novel role in EMT regulation and cancer progression.},
	year = {2019},
	eissn = {2073-4409},
	orcid-numbers = {Lakatos, Dóra/0000-0002-6461-5800; Hámori, Lilla/0000-0002-8962-0040; Róna, Gergely/0000-0003-3222-7261; Czirók, András/0000-0002-2694-5163; Füredi, András/0000-0002-7883-9901; Buday, László/0000-0003-3518-5757}
}

@article{MTMT:30761487,
	title = {Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing},
	url = {https://m2.mtmt.hu/api/publication/30761487},
	author = {Vas, Virág and Háhner, Tamás and Kudlik, Gyöngyi and Ernszt, Dávid and Kvell, Krisztián and Kuti, Dániel and Kovács, Krisztina and Tóvári, József and Trexler, Mária and Merő, Balázs László and Szeder, Bálint and Koprivanacz, Kitti and Buday, László},
	doi = {10.3390/cells8080831},
	journal-iso = {CELLS-BASEL},
	journal = {CELLS},
	volume = {8},
	unique-id = {30761487},
	abstract = {Obesity and adipocyte malfunction are related to and arise as consequences of disturbances in signaling pathways. Tyrosine kinase substrate with four Src homology 3 domains (Tks4) is a scaffold protein that establishes a platform for signaling cascade molecules during podosome formation and epidermal growth factor receptor (EGFR) signaling. Several lines of evidence have also suggested that Tks4 has a role in adipocyte biology; however, its roles in the various types of adipocytes at the cellular level and in transcriptional regulation have not been studied. Therefore, we hypothesized that Tks4 functions as an organizing molecule in signaling networks that regulate adipocyte homeostasis. Our aims were to study the white and brown adipose depots of Tks4 knockout (KO) mice using immunohistology and western blotting and to analyze gene expression changes regulated by the white, brown, and beige adipocyte-related transcription factors via a PCR array. Based on morphological differences in the Tks4-KO adipocytes and increased uncoupling protein 1 (UCP1) expression in the white adipose tissue (WAT) of Tks4-KO mice, we concluded that the beigeing process was more robust in the WAT of Tks4-KO mice compared to the wild-type animals. Furthermore, in the Tks4-KO WAT, the expression profile of peroxisome proliferator-activated receptor gamma (PPARγ)-regulated adipogenesis-related genes was shifted in favor of the appearance of beige-like cells. These results suggest that Tks4 and its downstream signaling partners are novel regulators of adipocyte functions and PPARγ-directed white to beige adipose tissue conversion.},
	keywords = {Adipogenesis; beige adipocytes; WAT browning; Tks4 scaffold protein},
	year = {2019},
	eissn = {2073-4409},
	orcid-numbers = {Kvell, Krisztián/0000-0001-8609-6274; Tóvári, József/0000-0002-5543-3204; Buday, László/0000-0003-3518-5757}
}

@article{MTMT:30628226,
	title = {Significance of the Tks4 scaffold protein in bone tissue homeostasis},
	url = {https://m2.mtmt.hu/api/publication/30628226},
	author = {Vas, Virág and Kovács, Tamás and Körmendi, Szandra Katalin and Bródy, Andrea and Kudlik, Gyöngyi and Szeder, Bálint and Mező, Diána and Kállai, Dóra and Koprivanacz, Kitti and Merő, Balázs László and Dülk, Metta and Tóvári, József and Vajdovich, Péter and Şenel, Ş Neslihan and Özcan, Ilknur and Helyes, Zsuzsanna and Dobó-Nagy, Csaba and Buday, László},
	doi = {10.1038/s41598-019-42250-6},
	journal-iso = {SCI REP},
	journal = {SCIENTIFIC REPORTS},
	volume = {9},
	unique-id = {30628226},
	issn = {2045-2322},
	abstract = {The main driver of osteoporosis is an imbalance between bone resorption and formation. The pathogenesis of osteoporosis has also been connected to genetic alterations in key osteogenic factors and dysfunction of bone marrow mesenchymal stem/stromal cells (BM-MSCs). Tks4 (encoded by the Sh3pxd2b gene) is a scaffold protein involved in podosome organization. Homozygous mutational inactivation of Sh3pxd2b causes Frank-ter Haar syndrome (FTHS), a genetic disease that affects bone tissue as well as eye, ear, and heart functions. To date, the role of Tks4 in adult bone homeostasis has not been investigated. Therefore, the aim of this study was to analyze the facial and femoral bone phenotypes of Sh3pxd2b knock-out (KO) mice using micro-CT methods. In addition to the analysis of the Sh3pxd2b-KO mice, the bone microstructure of an FTHS patient was also examined. Macro-examination of skulls from Tks4-deficient mice revealed craniofacial malformations that were very similar to symptoms of the FTHS patient. The femurs of the Sh3pxd2b-KO mice had alterations in the trabecular system and showed signs of osteoporosis, and, similarly, the FTHS patient also showed increased trabecular separation/porosity. The expression levels of the Runx2 and osteocalcin bone formation markers were reduced in the bone and bone marrow of the Sh3pxd2b-KO femurs, respectively. Our recent study demonstrated that Sh3pxd2b-KO BM-MSCs have a reduced ability to differentiate into osteoblast lineage cells; therefore, we concluded that the Tks4 scaffold protein is important for osteoblast formation, and that it likely plays a role in bone cell homeostasis.},
	year = {2019},
	eissn = {2045-2322},
	orcid-numbers = {Kovács, Tamás/0000-0003-4127-4545; Bródy, Andrea/0000-0001-8085-8418; Tóvári, József/0000-0002-5543-3204; Dobó-Nagy, Csaba/0000-0001-9530-7926; Buday, László/0000-0003-3518-5757}
}

@article{MTMT:30447936,
	title = {Structural insights into the tyrosine phosphorylation-mediated inhibition of SH3 domain-ligand interactions.},
	url = {https://m2.mtmt.hu/api/publication/30447936},
	author = {Merő, Balázs László and Radnai, László and Gógl, Gergő and Tőke, Orsolya and Leveles, Ibolya and Koprivanacz, Kitti and Szeder, Bálint and Dülk, Metta and Kudlik, Gyöngyi and Vas, Virág and Cserkaszky, Anna and Sipeki, Szabolcs and Nyitray, László and Vértessy, Beáta (Grolmuszné) and Buday, László},
	doi = {10.1074/jbc.RA118.004732},
	journal-iso = {J BIOL CHEM},
	journal = {JOURNAL OF BIOLOGICAL CHEMISTRY},
	volume = {294},
	unique-id = {30447936},
	issn = {0021-9258},
	abstract = {Src homology 3 (SH3) domains bind proline-rich linear motifs in eukaryotes. By mediating inter- and intramolecular interactions, they regulate the functions of many proteins involved in a wide variety of signal transduction pathways. Phosphorylation at different tyrosine residues in SH3 domains have been reported previously. In several cases, the functional consequences have also been investigated. However, a full understanding of the effects of tyrosine phosphorylation on the ligand interactions and cellular functions of SH3 domains requires detailed structural, atomic-resolution studies along with biochemical and biophysical analyses. Here, we present the first crystal structures of tyrosine-phosphorylated human SH3 domains derived from the Abelson-family kinases ABL1 and ABL2 at 1.6 and 1.4 Å resolutions, respectively. The structures revealed that simultaneous phosphorylation of Tyr-89 and Tyr-134 in ABL1, or the homologous residues Tyr-116 and Tyr-161 in ABL2 induce only minor structural perturbations. Instead, the phosphate groups sterically blocked the ligand-binding grooves, thereby strongly inhibiting the interaction with proline-rich peptide ligands. Although some crystal contact surfaces involving phosphotyrosines suggested the possibility of tyrosine-phosphorylation induced dimerization, we excluded this possibility by using small-angle X-ray scattering (SAXS), dynamic light scattering (DLS), and NMR relaxation analyses. Extensive analysis of relevant databases and literature revealed that the residues phosphorylated in our model systems are not only well conserved in other human SH3 domains, but that the corresponding tyrosines are known phosphorylation sites in vivo in many cases. We conclude that tyrosine phosphorylation might be a mechanism involved in the regulation of the human SH3 interactome.},
	keywords = {protein phosphorylation; X-RAY CRYSTALLOGRAPHY; ligand binding; nuclear magnetic resonance (NMR); ABL TYROSINE KINASE; 3BP-2; ABI2; Src homology 3 domain (SH3 domain); phosphotyrosine signaling; post translational modification (PTM)},
	year = {2019},
	eissn = {1083-351X},
	pages = {4608-4620},
	orcid-numbers = {Sipeki, Szabolcs/0000-0002-9678-6743; Nyitray, László/0000-0003-4717-5994; Buday, László/0000-0003-3518-5757}
}

@mastersthesis{MTMT:30619929,
	title = {A mesenchymalis őssejtek immunszuppresszív aktivitása},
	url = {https://m2.mtmt.hu/api/publication/30619929},
	author = {Kudlik, Gyöngyi},
	doi = {10.14753/SE.2018.2080},
	unique-id = {30619929},
	year = {2018}
}