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 - 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 - Hámori, Lilla AU - Kudlik, Gyöngyi AU - Szebényi, Kornélia AU - Kucsma, Nóra AU - Szeder, Bálint AU - Póti, Ádám AU - Uher, Ferenc AU - Várady, György AU - Szüts, Dávid AU - Tóvári, József AU - Füredi, András AU - Szakács, Gergely TI - Establishment and Characterization of a Brca1−/−, p53−/− Mouse Mammary Tumor Cell Line JF - INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES J2 - INT J MOL SCI VL - 21 PY - 2020 IS - 4 PG - 19 SN - 1661-6596 DO - 10.3390/ijms21041185 UR - https://m2.mtmt.hu/api/publication/31196937 ID - 31196937 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Budapest, 1117, Hungary Institute of Cancer Research, Medical University of Vienna, Vienna, 1090, Austria Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, 1097, Hungary Department of Experimental Pharmacology, National Institute of Oncology, Budapest, 1122, Hungary Export Date: 8 April 2020 Correspondence Address: Füredi, A.; Institute of Enzymology, Research Centre for Natural SciencesHungary; email: andras.fueredi@meduniwien.ac.at Funding details: Magyar Tudományos Akadémia, MTA, TUDFO/51757/2019‐ITM Funding details: K_124881, 2019‐1.3.1‐KK‐2019‐00007, K116295 Funding text 1: Funding: This research was funded by the National Research, Development and Innovation Fund of Hungary (2019‐1.3.1‐KK‐2019‐00007 to G.S. and A.F., K_124881 to D.S., and K116295 to J.T.) and a Momentum Grant from the Hungarian Academy of Sciences (G.S.). Financial support from the 2019 Thematic Excellence Program (TUDFO/51757/2019‐ITM) is also acknowledged. LA - English DB - MTMT ER - TY - JOUR AU - Szeder, Bálint AU - Tárnoki-Zách, Júlia AU - Lakatos, Dóra AU - Vas, Virág AU - Kudlik, Gyöngyi AU - Merő, Balázs László AU - Koprivanacz, Kitti AU - Bányai, László AU - Hámori, Lilla AU - Róna, Gergely AU - Czirók, András AU - Füredi, András AU - Buday, László TI - Absence of the Tks4 Scaffold Protein Induces Epithelial-Mesenchymal Transition-Like Changes in Human Colon Cancer Cells JF - CELLS J2 - CELLS-BASEL VL - 8 PY - 2019 IS - 11 PG - 18 SN - 2073-4409 DO - 10.3390/cells8111343 UR - https://m2.mtmt.hu/api/publication/30910673 ID - 30910673 N1 - Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, 1117, Hungary Department of Biological Physics, Eötvös University, Budapest, 1117, Hungary Department of Biochemistry and Molecular Pharmacology, New York University School of Medicine, New York, NY 10016, United States Department of Anatomy and Cell Biology, University of Kansas Medical Center, Kansas, KS 66160, United States University of Kansas Cancer Centre, Kansas, KS 66160, United States Institute of Cancer Research, Medical University of Vienna, Vienna, 1090, Austria Department of Medical Chemistry, Semmelweis University Medical School, Budapest, 1094, Hungary Cited By :9 Export Date: 14 November 2023 Correspondence Address: Tárnoki-Zách, J.; Department of Biological Physics, Hungary; email: zachjuli@yahoo.fr AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Vas, Virág AU - Háhner, Tamás AU - Kudlik, Gyöngyi AU - Ernszt, Dávid AU - Kvell, Krisztián AU - Kuti, Dániel AU - Kovács, Krisztina AU - Tóvári, József AU - Trexler, Mária AU - Merő, Balázs László AU - Szeder, Bálint AU - Koprivanacz, Kitti AU - Buday, László TI - Analysis of Tks4 Knockout Mice Suggests a Role for Tks4 in Adipose Tissue Homeostasis in the Context of Beigeing JF - CELLS J2 - CELLS-BASEL VL - 8 PY - 2019 IS - 8 PG - 16 SN - 2073-4409 DO - 10.3390/cells8080831 UR - https://m2.mtmt.hu/api/publication/30761487 ID - 30761487 N1 - Journal Article; Research Support, Non-U.S. Gov't Export Date: 4 May 2020 Funding Agency and Grant Number: National Research, Development, and Innovation Fund of Hungary [K 124045, FIEK_16-1-2016-0005, HunProEx 2018-1.2.1-NKP-2018-00005]; Hungarian Academy of SciencesHungarian Academy of Sciences; Ministry of Human Capacities [UNKP-18-3-III, UNKP-18-4 2018/2019]; PTE Pharmaceutical Talent Center [PTE AOK KA-2016-16]; [NKFIH K116295] Funding text: This research was funded by grants from the National Research, Development, and Innovation Fund of Hungary (K 124045, FIEK_16-1-2016-0005 and HunProEx 2018-1.2.1-NKP-2018-00005); the MedinProt Program of the Hungarian Academy of Sciences (LB); the NKFIH K116295 grant (JT); the UNKP-18-3-III New National Excellence Program of the Ministry of Human Capacities (ED); PTE AOK KA-2016-16 from the PTE Pharmaceutical Talent Center program (KK); the Janos Bolyai Scholarship of the Hungarian Academy of Sciences (KK); and Bolyai + 2018/2019 (UNKP-18-4 2018/2019 new national excellence program of the ministry of human capacities) (KK). The work of Virag Vas was supported by a Janos Bolyai Research Scholarship from the Hungarian Academy of Sciences. AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Vas, Virág AU - Kovács, Tamás AU - Körmendi, Szandra Katalin AU - Bródy, Andrea AU - Kudlik, Gyöngyi AU - Szeder, Bálint AU - Mező, Diána AU - Kállai, Dóra AU - Koprivanacz, Kitti AU - Merő, Balázs László AU - Dülk, Metta AU - Tóvári, József AU - Vajdovich, Péter AU - Şenel, Ş Neslihan AU - Özcan, Ilknur AU - Helyes, Zsuzsanna AU - Dobó-Nagy, Csaba AU - Buday, László TI - Significance of the Tks4 scaffold protein in bone tissue homeostasis JF - SCIENTIFIC REPORTS J2 - SCI REP VL - 9 PY - 2019 IS - 1 PG - 10 SN - 2045-2322 DO - 10.1038/s41598-019-42250-6 UR - https://m2.mtmt.hu/api/publication/30628226 ID - 30628226 AB - 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. LA - English DB - MTMT ER - TY - JOUR AU - Merő, Balázs László AU - Radnai, László AU - Gógl, Gergő AU - Tőke, Orsolya AU - Leveles, Ibolya AU - Koprivanacz, Kitti AU - Szeder, Bálint AU - Dülk, Metta AU - Kudlik, Gyöngyi AU - Vas, Virág AU - Cserkaszky, Anna AU - Sipeki, Szabolcs AU - Nyitray, László AU - Vértessy, Beáta (Grolmuszné) AU - Buday, László TI - Structural insights into the tyrosine phosphorylation-mediated inhibition of SH3 domain-ligand interactions. JF - JOURNAL OF BIOLOGICAL CHEMISTRY J2 - J BIOL CHEM VL - 294 PY - 2019 IS - 12 SP - 4608 EP - 4620 PG - 13 SN - 0021-9258 DO - 10.1074/jbc.RA118.004732 UR - https://m2.mtmt.hu/api/publication/30447936 ID - 30447936 N1 - Institute of Enzymology, Magyar tudósok körútja 2, Budapest, H-1117, Hungary Laboratory for NMR Spectroscopy, Research Center for Natural Sciences (RCNS), Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, H-1117, Hungary Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, Budapest, H-1117, Hungary Department of Applied Biotechnology and Food Sciences, Budapest University of Technology and Economics, Szt. Gellért tér 4, Budapest, H-1111, Hungary Department of Medical Chemistry, Semmelweis University Medical School, Tuzoltó u. 37– 47, Budapest, H-1094, Hungary Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, H-1117, Hungary Export Date: 9 July 2019 CODEN: JBCHA Correspondence Address: Radnai, L.; Dept. of Molecular Medicine, Scripps Research Institute, 130 Scripps Way, United States; email: lradnai@scripps.edu Institute of Enzymology, Magyar tudósok körútja 2, Budapest, H-1117, Hungary Laboratory for NMR Spectroscopy, Research Center for Natural Sciences (RCNS), Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, H-1117, Hungary Department of Biochemistry, Eötvös Loránd University, Pázmány Péter sétány 1/C, Budapest, H-1117, Hungary Department of Applied Biotechnology and Food Sciences, Budapest University of Technology and Economics, Szt. Gellért tér 4, Budapest, H-1111, Hungary Department of Medical Chemistry, Semmelweis University Medical School, Tuzoltó u. 37– 47, Budapest, H-1094, Hungary Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Magyar tudósok körútja 2, Budapest, H-1117, Hungary Export Date: 10 July 2019 CODEN: JBCHA Correspondence Address: Radnai, L.; Dept. of Molecular Medicine, Scripps Research Institute, 130 Scripps Way, United States; email: lradnai@scripps.edu AB - 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. LA - English DB - MTMT ER - TY - THES AU - Kudlik, Gyöngyi TI - A mesenchymalis őssejtek immunszuppresszív aktivitása PY - 2018 DO - 10.14753/SE.2018.2080 UR - https://m2.mtmt.hu/api/publication/30619929 ID - 30619929 LA - Hungarian DB - MTMT ER -