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TATIANA UGAROVA Associate Professor Ph.D., Institute of Biochemistry, National Academy of Sciences of the USSR, Kiev Send e-mail to Tatiana.Ugarova@asu.edu

Background

Prior to joining ASU, Dr. Ugarova was an assistant professor in the Lerner College of Medicine of Case Western Reserve University and a staff scientist in the Center for Thrombosis and Vascular Biology at the Cleveland Clinic Foundation. She received her training in the Temple University School of Medicine, Philadelphia, and later was a research fellow in the Scripps Research Institute, La Jolla.

Role of Integrins in Cell Adhesion and Migration

Our laboratory studies the structure, function and physiology of integrin receptors. Integrins are the dominant class of receptors employed by cells to mediate adhesion between cells and the extracellular matrix. These receptors are involved in a variety of fundamental cellular functions such as cell migration, cell division and differentiation. Integrin-mediated adhesion also initiates such specialized cellular responses as inflammation, angiogenesis and hemostasis. Aberrations in integrin function underlie the pathogenesis of many diseases, including tumor growth and metastasis, thrombosis and chronic inflammation. Therefore, integrins are important targets in the design of drugs for treatment of these diseases.

The major focus in the laboratory is the group of β2 integrins which regulate an influx of leukocytes from blood to sites of inflammation and which play a central role in the inflammatory response and host defense. Integrins as a group exhibit broad ligand specificity and the major neutrophil and monocyte integrin α_Mβ₂ (Mac-1, CD11b/CD18) is the most promiscuous member of the entire family. Our aims are to understand the mechanisms which allow α_Mβ₂ to exhibit broad ligand specificity and to elucidate its biological significance. Cell and molecular biology, peptide libraries and bioinformatics approaches are used to determine the molecular basis for integrin α_Mβ₂'s extreme "stickiness".

In functional in vitro and in vivo studies, we are testing the hypothesis that progressive upregulation of α_Mβ₂ on the surface of neutrophils by translocation from internal pools as well as its capacity to bind numerous proteins in the extracellular matrix control an overall process of neutrophil migration. Other studies in the lab are focused on understanding the role of recently discovered integrin α_Dβ₂, an adhesion receptor upregulated in macrophage foam cells in atherosclerotic lesions. Our in vitro analyses employ engineered cells expressing recombinant integrins as well as leukocyte cell lines and isolated blood cells. In our in vivo studies we use mice in which expression of leukocyte integrins is altered by agents which induce the inflammatory response.

Another project examines signaling through integrins. The major platelet integrin α_IIbβ₃ (GPIIb-IIIa), which plays critical roles in normal hemostasis and pathological thrombosis, serves as a model for these studies. We are exploring the role of this integrin cytoplasmic domains in the initiation of intracellular signaling. In particular, this work investigates how the integrin cytoplasmic tails interact with cytoplasmic proteins to induce reorganization of the cytoskeleton.

Selected Publications

Lishko, V.K, Burke, T. and Ugarova, T.P Anti-adhesive effect of fibrinogen: A safeguard for thrombus stability. Blood 2006, Jul 18; [Epub ahead of print].

Podolnikova, N. P., Gorkun, O.V., Loreth, R.M., Lord, S.T., Yee, V.C. and Ugarova, T.P. A cluster of basic amino acid residues in the γ370-381 sequence of fibrinogen comprises a binding site for platelet integrin α_IIbβ₃ (GPIIb/IIIa). 2005, Biochemistry, 44, 51, 16920-16930.

Yakubenko, V.P., Yadav, S.P. and Ugarova, T.P. Integrin α_Dβ₂, an adhesion receptor upregulated in macrophage foam cells, exhibits multiligand binding properties. 2005, Blood 107, 1643-1650.

Lishko, V., Podolnikova, N., Yakubenko, V., Yakovlev, S., Medved, L., Yadav, S., Ugarova, T.P. Multiple binding sites in fibrinogen for integrin α_Mβ₂ (Mac-1). J Biol Chem. 2004, 279, 44897-44906.

Lishko, V.K., Novokhatny V., Yakubenko, V.P., Skomorovskaja-Prokvolit, H., Ugarova, T.P. Characterization of plasminogen as an adhesive ligand for integrins α_Mβ₂ (Mac-1) and α₅β₁(VLA-5). Blood, 2004, Blood, 2004 104(3):719-26.

Schober, J.M., Lester F., Lau, Ugarova, T.P., Lam, S.C.-T. Identification of a novel integrin α_Mβ₂ binding site in CCN1 (CYR61), a matricellular protein expressed in healing wounds and atherosclerotic lesions. J. Biol. Chem. 2003, 278, 25808-25815.

Podolnikova, N.P., Yakubenko, V.P., Plow, E.F. and Ugarova, T.P. Identification of a novel binding site for platelet integrins α_IIbβ₃ (GPIIbIIIa) and α₅β₁ in the C-domain of fibrinogen. J. Biol. Chem. 2003, 278, 32251-32258.

Ugarova, T.P., Lishko, V.K., Podolnikova, N., Okumura, N., Merkulov, S., Yakubenko, V.P., Yee, V.C., Lord, S.T., Haas, T.A. Sequence γ383-395 (P2-C) but not γ190-202 (P1) is binding site for the α_MI-domain of integrin α_Mβ₂ in the γC-domain of fibrinogen. Biochemistry, 2003, 42, 9365-9373.

Yakubenko, V.P., Lishko, V.K., Lam, S.-C. and Ugarova, T.P. A molecular basis for inetgrin α_Mβ₂ ligand binding promiscuity. J. Biol. Chem. 2002, 277, 48635-48642.

Lishko, V.K., Yakubenko, V.P. and Ugarova, T.P. The interplay between integrins α_Mβ₂ and α₅β₁ during cell migration to fibronectin. Exp. Cell Research 2003, 283, 116-126 (also Editorial comments).

Lishko, V.K., Kudryk, B.J., Yee, V.C. and Ugarova, T.P. Regulated exposure of the cryptic binding site for leukocyte integrin α_Mβ₂ in the γC-domain of fibrinogen. Biochemistry 2002, 41, 12942-12951.

Lishko, V.K., Yakubenko, V.P., Hertzberg, K.M, Grieninger, G. and Ugarova, T.P. The alternatively spliced EC domain of fibrinogen-420 is a novel ligand for leukocyte integrins α_Mβ₂ and α_xβ₂ integrins. Blood, 2001, 98, 2448-2455.

Hu, W.J., Eaton, J.W., Ugarova, T.P. and Tang, L. Molecular basis of biomaterial-mediated foreign body reactions. Blood, 2001, 98, 1231-1238

Forsyth, C.B., Solovjov, D.A., Ugarova, T.P. and Plow, E.F. Integrin α_Mβ₂-mediated cell migration to fibrinogen and recognition peptides. J. Exp. Med. 2001, 193, 1-12.

Yakubenko, V.P., Solovjov, D.A., Zhang, L., Yee, V.C., Plow, E.F. and Ugarova, T.P. Identification of the binding site for fibrinogen recognition peptide γ383-395 within the α_MI- domain of integrin α_Mβ₂. J. Biol. Chem. 2001, 276, 17, 13995-14003.

Ugarova T.P., Yakubenko V.P. Recognition of fibrinogen by leukocyte integrins: a molecular link between hemostasis and inflammation. Ann. New York Acad. Sci., 2001, 936, 368-386.

Yakubenko, V.P., Lobb, R.R., Plow, E.F., Ugarova, T.P. Differential induction of gelatinase B (MMP-9) and gelatinase A (MMP-2) in T-lymphocytes through α4β1-mediated adhesion to VCAM-1 and the CS-1 peptide of fibronectin. Exp. Cell. Res. 2000, 260, 73- 84.

McClary, K.B., Ugarova, T.P., Grainger, D.W. Modulating fibroblast adhesion, spreading and proliferation using self-assembled monolayer films of alkylthiolates on gold. Journal of Biomedical Materials Research. 2000, 50, 428-439.

Shih, P.T., Elices, M.J., Fang, Z., Ugarova, T.P., Strahl, D., et al., Minimally modified low-density lipoprotein induces monocyte adhesion to endothelial connecting segment-1 by activating β1 integrin. J. Clin. Invest. 1999, 103: 613-625.

Ugarova, T.P., Solovjov, D.A., Zhang, L., Loukinov, D.I., Yee, V.C., Medved, L.V., Plow, E.F. Identification of a novel recognition sequence for integrin α_Mβ₂ within the γ-chain of fibrinogen. J. Biol. Chem. 273:22519-22527, 1998.