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Department of Biochemistry and Molecular Medicine

Department of Biochemistry and Molecular Medicine

Yoshikazu Takada, M.D., Ph.D.

Yoshikazu Takada, M.D., Ph.D.

Professor
3300, 4645 Second Ave.,
Sacramento, CA 95817
e-mail

Laboratory Personnel

Massaki Fujita, M.D., Ph.D.

Parastoo Davari, M.D.

Puneet Kumar, Ph.D.

Tiffany Dickerson, B.A.

Jessica Yu

Yoko K. Takada

Dora Cedano Prieto

Research Interests

Yoshikazu Takada, M.D., Ph.D. was involved in identifying and characterizing several of the â1 integrins (VLA proteins) in the 1980s. He cloned the α2, α3, and α4 subunits and identified collagen, laminin, and vascular cell adhesion molecule-1 as their respective ligands. Dr. Takada also performed structure-function studies of several integrins using site-directed mutagenesis, particularly in the putative ligand-binding sites of integrins. His results were consistent with the crystal structure of the integrin αvβ3-RGD complex and helped interpret the integrin structure. Dr. Takada currently focuses on integrin-growth factor crosstalk. His group discovered the direct binding of integrins to FGF1, and determined that this interaction plays a critical role in FGF signaling. Most recently, they discovered that IGF-1 (insulin-like growth factor-1) directly binds to integrins and this interaction is involved in IGF/IGF1R signaling. These findings suggest that direct integrin binding is involved in growth factor signaling. It has been well established that integrins are involved in growth factor signaling, since antagonists to integrins suppress growth factor signaling. Dr. Takada’s current model of growth factor-integrin crosstalk is that 1) integrins interact with extracellular matrix (ECM) and growth factors bind to growth factor receptors, and 2) two separate signals merge together inside the cells to induce intracellular signals. He proposes that direct integrin binding to growth factors (e.g., IGF, neuregulin and FGF) plays a role in the crosstalk.

 

Representative Publications

Xiao W, Wang Y, Lau EY, Luo J, Yao N, Shi C, Meza L, Tseng H, Maeda Y, Kumaresan P, Liu R, Lightstone FC, Takada Y, Lam KS. The Use of One-Bead One-Compound Combinatorial Library Technology to Discover High-Affinity {alpha}v{beta}3 Integrin and Cancer Targeting Arginine-Glycine-Aspartic Acid Ligands with a Built-in Handle. Mol Cancer Ther. 2010 Sep 21. [Epub ahead of print]PMID: 20858725

Ieguchi K, Fujita M, Ma Z, Davari P, Taniguchi Y, Sekiguchi K, Wang B, Takada YK, Takada Y. Direct Binding of the EGF-like Domain of Neuregulin-1 to Integrins ({alpha}v{beta}3 and {alpha}6{beta}4) Is Involved in Neuregulin-1/ErbB Signaling. J Biol Chem. 2010 Oct 8;285(41):31388-98.

Yamaji S, Saegusa J, Ieguchi K, Fujita M, Takada YK, Takada Y. A novel fibroblast growth factor-1 (FGF1) mutant that acts as an FGF antagonist. PLoS One. 2010 Apr 21;5(4):e10273.PMID: 20422052

Takada Y, Ono Y, Saegusa J, Mitsiades C, Mitsiades N, Tsai J, He Y, Maningding E, Coleman A, Ramirez-Maverakis D, Rodriquez R, Takada Y, Maverakis E. A T cell-binding fragment of fibrinogen can prevent autoimmunity. J Autoimmun. 2010 Jun;34(4):453-9. Epub 2009 Dec 24.PMID: 20036106

Saegusa J, Yamaji S, Ieguchi K, Wu CY, Lam KS, Liu FT, Takada YK, Takada Y. The direct binding of insulin-like growth factor-1 (IGF-1) to integrin alphavbeta3 is involved in IGF-1 signaling. J Biol Chem. 2009 Sep 4;284(36):24106-14. Epub 2009 Jul 3.PMID: 19578119

Guo M, Daines D, Tang J, Shen Q, Perrin RM, Takada Y, Yuan SY, Wu MH. Fibrinogen-gamma C-terminal fragments induce endothelial barrier dysfunction and microvascular leak via integrin-mediated and RhoA-dependent mechanism. Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):394-400. Epub 2009 Jan 2.PMID: 19122172

Yao N, Xiao W, Wang X, Marik J, Park SH, Takada Y, Lam KS. Discovery of targeting ligands for breast cancer cells using the one-bead one-compound combinatorial method. J Med Chem. 2009 Jan 8;52(1):126-33.PMID: 19055415

Saegusa J, Akakura N, Wu CY, Hoogland C, Ma Z, Lam KS, Liu FT, Takada YK, Takada Y. Pro-inflammatory secretory phospholipase A2 type IIA binds to integrins alphavbeta3 and alpha4beta1 and induces proliferation of monocytic cells in an integrin-dependent manner. J Biol Chem. 2008 Sep 19;283(38):26107-15. Epub 2008 Jul 17.PMID: 18635536

Mori S, Wu CY, Yamaji S, Saegusa J, Shi B, Ma Z, Kuwabara Y, Lam KS, Isseroff RR, Takada YK, Takada Y. Direct binding of integrin alphavbeta3 to FGF1 plays a role in FGF1 signaling. J Biol Chem. 2008 Jun 27;283(26):18066-75. Epub 2008 Apr 25.PMID: 18441324

Versteeg HH, Schaffner F, Kerver M, Petersen HH, Ahamed J, Felding-Habermann B, Takada Y, Mueller BM, Ruf W. Inhibition of tissue factor signaling suppresses tumor growth. Blood. 2008 Jan 1;111(1):190-9. Epub 2007 Sep 27.PMID: 17901245

Takada Y, Ye X, Simon S. The integrins. Genome Biol. 2007;8(5):215. Review.PMID: 17543136

Fleming FE, Graham KL, Taniguchi K, Takada Y, Coulson BS. Rotavirus-neutralizing antibodies inhibit virus binding to integrins alpha 2 beta 1 and alpha 4 beta 1. Arch Virol. 2007;152(6):1087-101. Epub 2007 Feb 23.PMID: 17318737

Akakura N, Hoogland C, Takada YK, Saegusa J, Ye X, Liu FT, Cheung AT, Takada Y. The COOH-terminal globular domain of fibrinogen gamma chain suppresses angiogenesis and tumor growth. Cancer Res. 2006 Oct 1;66(19):9691-7.PMID: 17018627

Peng L, Liu R, Marik J, Wang X, Takada Y, Lam KS. Combinatorial chemistry identifies high-affinity peptidomimetics against alpha4beta1 integrin for in vivo tumor imaging. Nat Chem Biol. 2006 Jul;2(7):381-9. Epub 2006 Jun 11.PMID: 16767086

Graham KL, Takada Y, Coulson BS. Rotavirus spike protein VP5* binds alpha2beta1 integrin on the cell surface and competes with virus for cell binding and infectivity. J Gen Virol. 2006 May;87(Pt 5):1275-83.PMID: 16603530

Tarui T, Akakura N, Majumdar M, Andronicos N, Takagi J, Mazar AP, Bdeir K, Kuo A, Yarovoi SV, Cines DB, Takada Y. Direct interaction of the kringle domain of urokinase-type plasminogen activator (uPA) and integrin alpha v beta 3 induces signal transduction and enhances plasminogen activation. Thromb Haemost. 2006 Mar;95(3):524-34.PMID: 16525582

Wu PL, Lee SC, Chuang CC, Mori S, Akakura N, Wu WG, Takada Y. Non-cytotoxic cobra cardiotoxin A5 binds to alpha(v)beta3 integrin and inhibits bone resorption. Identification of cardiotoxins as non-RGD integrin-binding proteins of the Ly-6 family. J Biol Chem. 2006 Mar 24;281(12):7937-45. Epub 2006 Jan 10.PMID: 16407244

Graham KL, Fleming FE, Halasz P, Hewish MJ, Nagesha HS, Holmes IH, Takada Y, Coulson BS. Rotaviruses interact with alpha4beta7 and alpha4beta1 integrins by binding the same integrin domains as natural ligands. J Gen Virol. 2005 Dec;86(Pt 12):3397-408.PMID: 16298987

Thodeti CK, Fröhlich C, Nielsen CK, Takada Y, Fässler R, Albrechtsen R, Wewer UM. ADAM12-mediated focal adhesion formation is differently regulated by beta1 and beta3 integrins. FEBS Lett. 2005 Oct 24;579(25):5589-95. Epub 2005 Sep 28.PMID: 16213489