Head:             Gergely Pál, PhD, DSc, MHAS 

Coworkers:       Bakó Éva, PhD

                        Róza Zákány, PhD

                        Csaba Matta, PhD

                        Tamás Juhász, PhD

                        Docsa Tibor

                        Kolozsvári Bernadett

                        Dembrovszkiné Kovács Ella

                                

The Signal Transfer Group comprises 10 scientists and support staff in 3 research topics studying different aspects of the role of protein phosphorylation in human health and disease.

Reversible protein phosphorylation is a key determinant in many fundamental cellular functions, such as survival, differentiation, structural organization, and stress responses. The reversibility of protein phosphorylation is the result of the coordinated enzymatic activities of different protein kinases and phosphatases. We are especially interested in phosphorylation-dephosphorylation mediated signalling that maintains normal cellular and structural homeostasis, and how disturbances in the processing and integration of this type of signalling are reflected as alterations in cellular differentiation and organization.

 

The major interest with respect to cancer cells is how protein phosphatases may influence the proliferation, survival, death and motility of these cells. It is also an important question what role of protein phosphatases may play in influencing the effects of chemotherapeutic drugs designed to induce cell death of cancer cells. Novel knowledge on this field may have clinical applications too, and could focus attention on the protein phosphatases as possible drug targets. The following aims are investigated within the frame of this research project.

Dissection of the role of PP1, PP2A and PP2B in the survival and death of malignant cells: study of the involvement of PP1, PP2A and PP2B catalyzed dephosphorylation processes in chemosensitivity and resistance.

Identification and characterization of novel PP1 inhibitory proteins in malignant cells: study of the structure-inhibitory potency relationship of these proteins.

Study of the mechanism of localization, translocation and drug induced phosphorylation of phosphatase regulatory subunits.
Investigation of the role of PP1, PP2A and PP2B in the motile properties of the melanoma cell lines with special emphasis on changes of actin-cytoskeleton and the involvement of different types of myosin phosphatases.

Study of the complex regulatory mechanism including PP1, PP2B, PP2A and their possible target molecules influencing viability, proliferation and nuclear Ca2+-signaling of normal human epidermal melanocytes and variable melanoma cell lines.

II. Protein Kinases and Phosphatases in the Regulation of Chondrogenesis

Skeletal elements of vertebrate limb both in vivo and in vitro are derived from mesenchymal cells. Parallel with an initial very intense proliferation, these cells condense to form prechondrogenic cell aggregates, differentiate into mature chondrocytes and start to express cartilage-specific extracellular matrix molecules. We have evaluated the importance of the Ser/Thr protein phosphorylation and dephosphorylation for chondrogenesis in high-density chicken limb bud mesenchymal cell cultures by using cell-permeable protein kinase and phosphatase inhibitors. The current research interest is to identify and characterize further protein kinases and phosphatases that participate in the signal transduction networks, and to discover how they regulate differentiation in response to extracellular signals, such as growth factors, cytokines and cell damaging agents.

 

Non-insulin dependent diabetes mellitus (NIDDM) or type 2 diabetes is characterized by impaired glucose tolerance and is associated with other pathological conditions of insulin resistance and obesity. Glycogen phosphorylase has been exploited as a potential target for inhibitors that might prevent glycogenolysis under high glucose conditions in type 2 diabetes. Our research focuses on the following general objectives: (1) understand molecular recognition of small molecules (inhibitors) by glycogen phosphorylase, and (2) explore how this knowledge may be used for the design of potential hypoglycaemic drugs by employing a combination of chemical syntheses, kinetic and biological experiments, X-ray crystallographic methods, modelling studies and molecular dynamics simulations.

 

I.F. Pelyvás, Z.G. Tóth, Gy. Vereb, A. Balla, E. Kovács, A. Gorzás, F. Sztaricskai, P. Gergely: Synthesis of new cyclytol compounds influencing the activity of phosphatydil-inositol 4-kinase isoform, PI4K230. J. Med. Chem. 44, 627-632 (2001)

S. Sipka, K. Szűcs, S. Szántó, I. Kovács, G. Lakos, E. Vissi, P. Antal-Szalmás, Gy. Szegedi, P. Gergely: Glucocorticosteroid induced decrease in the activity of calcineurin in the peripherial blood mononuclear cells of patients with systemic lupus erythematosus. Ann. Rheumatol. Dis. 60, 380-384 (2001)

L. Somsák, L. Kovács, M. Tóth, E. Ősz, L. Szilágyi, Z. Györgydeák, Z. Dinya, T. Docsa, B. Tóth, P. Gergely: Synthesis of and a comparative study on the inhibition of muscle and liver glycogen phosphorylases by epimeric pairs of D-gluco- and D-xylopyranosy-lidene-spiro-(thio)hydantoins and a-(D-glucopyranosyl) amides. J. Med. Chem. 44, 2843-2848 (2001)

S. Sipka, S. Szántó, K. Szűcs, I. Kovács, E. Kiss, P. Antal-Szalmás, G. Lakos, M. Aleksza, Á. Illés, P. Gergely, G. Szegedi: Decreased arachidonic acid release in peripheral blood monocytes of patients with systemic lupus erythematosus. J. Rheumatol. 28, 2012-2017 (2001)

N.G. Oikonomakos, V.T. Skamnaki, E. Ősz, L. Szilágyi, L. Somsák, T. Docsa, B. Tóth, P. Gergely: Kinetic and crystallographic studies of glucopyranosylidene spirothiohydantoin binding to glycogen phosphorylase b. Bioorg. Med. Chem. 10, 261-268 (2002)

N. G. Oikonomakos,M. Kosmopoulou,S.E. Zographos,D.D. Leonidas,L. Somsák,V. Nagy,J.-P. Praly, T. Docsa,B. Tóth,P. Gergely: The binding of N-acetyl- and N-benzoyl-N’-b-D-glucopyranosyl ureas to glycogen phosphorylase b: Kinetic and crystallographic studies. Eur. J. Biochem. 269, 1684-1696 (2002)

R. Zákány, K. Szűcs, É. Bakó, S. Felszeghy, G. Czifra, T. Bíró, L. Módis, P. Gergely: Protein phosphatase 2A is involved in the regulation of protein kinase A pathway During in vitro chondrogenesis. Exp. Cell Res. 275, 1-8 (2002)

L. Somsák, V. Nagy, Zs. Hadady, T. Docsa, P. Gergely: Glucose analog inhibitors of glycogen phosphorylases as potential antidiabetic agents: recent developments. Curr. Pharm. Design 9, 117-1189 (2003)

Z. Györgydeák, Z. Hadady, N. Felföldi, A. Krakomperger, V. Nagy, M. Tóth, A. Brunyanszki, T. Docsa, P. Gergely, L. Somsák: Synthesis of N-(beta-D-glucopyranosyl)- and N-(2-acetamido-2-deoxy-beta-D-glucopyranosyl) amides as inhibitors of glycogen phosphorylase. Bioorg. Med. Chem. 12, 4861-4870 (2004)

T. Biró, Z. Griger, E. Kiss, H. Papp, M. Aleksza, I. Kovács, M. Zeher, E. Bodolay, T. Csépány, K. Szűcs, P. Gergely, L. Kovács, G. Szegedi, S. Sipka: Abnormal cell-specific expressions of certain protein kinase C isoenzymes in peripheral mononuclear cells of patients with systemic lupus erythematosus: effect of corticosteroid application. Scand. J. Immunol. 60, 421-428 (2004)

E.D. Chrysina, M.N. Kosmopoulou, C. Tiraidis, R. Kardakaris, N. Bischler, D.D. Leonidas, Z. Hadady, L. Somsák, T. Docsa, P. Gergely, N.G. Oikonomakos: Kinetic and crystallographic studies on 2-({beta}-D-glucopyranosyl)-5-methyl-1, 3, 4-oxadiazole, -benzothiazole, and -benzimidazole, inhibitors of muscle glycogen phosphorylase b. Evidence for a new binding site. Protein Sci. 14, 873-888 (2005)

R. Zákány, Z. Szíjgyártó, C. Matta, T. Juhász, C. Csortos, K. Szűcs, G. Czifra, T. Bíró, L. Módis, P. Gergely: Hydrogen peroxide inhibits formation of cartilage in chicken micromass cultures and decreases the activity of calcineurin: implication of ERK1/2 and Sox9 pathways. Exp Cell Res. 305,190-199 (2005)

ErdélyiK. Erdélyi, E. Bakondi, P. Gergely, C. Szabo, L.Virág: Pathophysiologic role of oxidative stress-induced poly(ADP-ribose) polymerase-1 activation: focus on cell death and transcriptional regulation. Cell Mol Life Sci. 62, 751-759 (2005)

Kiss A., Bakondi E., Bai P., Szabo C., Gergely P., Erdődi F., Virág L.: Gallotannin inhibits the expression of chemokines and inflammatory cytokines in A549 cells. Mol. Pharmacol. 68, 895-904 (2005)

Lontay B., Kiss A., Gergely P., Hartshorne D.J., Erdődi F.: Okadaic acid induces phosphorylation and translocation of myosin phosphatase target subunit 1 influencing myosin phosphorylation, stress fiber assembly and cell migration in HepG2 cells. Cell Signal. 17, 1265.1275 (2005)

L. Somsák, V. Nagy, Zs. Hadady, N. Felföldi, T. Docsa, P. Gergely: Recent developments in the synthesis and evaluation of lucose analog inhibitors of glycogen phosphorylases as potential antidiabetic agents. Frontiers in Medicinal Chemistry 2, 253-272 (2005)

E. Anagoustou, M.N Kosmopoulou, E.D. Chrysina, D.D. Leonidas, T. Hadjiloi, C. Tiriadis, S.E. Zographos, Z. Györgydeák, L. Somsák, T. Docsa, P. Gergely, F.N. Kosilis, N.G. Oikonomakos: Crystallographic studies on two bioisosteric analogues, N-acetyl-beta-d-glucopyranosylamine and N-trifluoroacetyl-beta-d-glucopyranosylamine, potent inhibitors of muscle glycogen phosphorylase. Bioorg. Med. Chem.14, 181-189 (2006)

K. Czifrák, Zs. Hadady, T. Docsa, P. Gergely, J. Schmidt6, L. Wessjohann, L. Somsák: Synthesis of N-(ß-D-glucopyranosyl) monoamides of dicarboxylic acids as potential inibitors of glycogen phosphorylase. Carbohydrate Res. 341, 947-956 (2006)

M. Bentlifa, S. Vidal, B. Fenet, M. Msaddek, P.G. Goekjian, J-P. Praly, A. Brunyánszki, T. Docsa, P. Gergely: In search of glycogen phosphorylase inhibitors: 5-substituted 3-C-glucopyranosyl-1,2,4-oxadiazoles from ß-D.glucopyranosyl cyanides upon cyclization of O-acylamidoxime intermediates. Eur. J. Org. Chem. 18, 4242-4256 (2006)

Kakuk, A., Friedlander, E., Vereb, Gy. Jr., Kása, A., Balla, A., Balla, T., Heilmeyer, L.M.G., Gergely, P., Vereb, Gy.: Nucleolar localization of phosphatidylinositol 4-kinase PI4K230 in various mammalian cells. International Society for Analytical Cytology 69A, 1174-1183 (2006)

Zákány, R., Bakondi, E., Juhász, T., Matta, Cs., Szíjgyártó, Zs., Erdélyi, K., Szabó, É., Módis, L., Virág, L., Gergely, P.: Oxidative stress-induced poly(ADP-ribosyl)ation in chick limb bud-derived chondrocytes. Int. J. Mol. Med. 4, 597-605 (2007)

Szijgyártó Z., Szucs K., Kovács I., Zákány R., Sipka S., Gergely P.: The role of protein kinase C isoenzymes in the regulation of calcineurin activity in human peripheral blood mononuclear cells. Int J Mol Med. 20, 359-364 (2007)

Kakuk, A., Friedlander, E., Vereb, Gy. Jr, Lisboa, D., Bagossi, P., Tóth, G., Gergely, P., Vereb, Gy.: Nuclear and nucleolar localization signals and their targeting function in phosphatidylinositol 4-kinase PI4K230. Exp. Cell Research 314, 2376-2388 (2008)