Biomedical Research Education &
Takahashi, Takamune, M.D., Ph.D.
Associate Professor of Medicine
Associate Professor of Cancer Biology
|Ph.D., Jikei University School of Medicine
M.D., Jikei University School of Medicine
S-3223 MCN 37232-2372
Tyrosine Phosphatase, Endothelial Cells, Angiogenesis, Renal Biology and Pathology, Diabetic Nephropathy, Endothelial Nitric Oxide Synthase
Molecular Basis of Angiogenesis, Renal Biology and Pathology, Endothelial Pathology
Angiogenesis, formation of new blood vessels, is a pivotal process in organogenesis and tissue regeneration, requiring ordered endothelial cell proliferation, migration, and homotypic and heterotypic intercellular adhesion. However, when angiogenesis is induced (and unregulated) in pathological conditions, it greatly contributes to the progression of disease, including cancer, diabetes, ischemic, and inflammatory disorders. Thus, definition of the intrinsic molecular controls that regulate angiogenic vessel growth promises novel therapeutic approaches for angiogenesis-associated diseases.
In the recent decades, investigators have identified various endothelial cell surface receptors and their activating ligands that promote and coordinate angiogenic vessel formation. However, much less is known about the endothelial receptors that transduce "anti-angiogenic (or angiostatic)" signals, though they could be used for angiogenesis inhibition. CD148 (DEP-1/PTPeta) is a transmembrane tyrosine phosphatase which is abundantly expressed in vascular endothelial cells of various tissues. We have shown that CD148 suppresses endothelial growth factor signals and strongly inhibits endothelial cell growth in culture and in vivo. Further, we have recently found that thrombospondin-1 (TSP-1) serves as an agonistic ligand for CD148. We are currently determining: 1. the role of CD148 in postnatal angiogenesis (physiological and pathological); 2. the role of TSP-1 and CD148 interaction in angiogenesis. These efforts should explore new pathways of angiogenesis inhibition and provide a novel strategy for anti-angiogenesis therapy.
Another project in the lab examines the mechanisms of diabetic renal microvascular injury. We found that loss of eNOS or SOD enzyme largely exacerbates diabetic glomerular microvascular injury in mice. The lab examines the detailed mechanisms of this using conditional as well as global knockout mouse.
Last, as a primary lab of Vanderbilt O???Brien Mouse Kidney Physiology and Disease Center (MKPDC), the lab and VUIIS scientists are developing non-invasive kidney imaging techniques that enable structural, functional, and molecular assessments of mouse kidney disease in living animals.
Fujita, H, Fujishima, H, Takahashi, K, Sato, T, Shimizu, T, Morii, T, Shimizu, T, Shirasawa, T, Qi, Z, Breyer, MD, Harris, RC, Yamada, Y, Takahashi, T. SOD1, but not SOD3, deficiency accelerates diabetic renal injury in C57BL/6-Ins2(Akita) diabetic mice. Metabolism, 2012
Jiang, R, Wang, S, Takahashi, K, Fujita, H, Fruci, CR, Breyer, MD, Harris, RC, Takahashi, T. Generation of a conditional allele for the mouse endothelial nitric oxide synthase gene. Genesis, 50(9), 685-92, 2012
Takahashi, K, Mernaugh, RL, Friedman, DB, Weller, R, Tsuboi, N, Yamashita, H, Quaranta, V, Takahashi, T. Thrombospondin-1 acts as a ligand for CD148 tyrosine phosphatase. Proc Natl Acad Sci U S A, 109(6), 1985-90, 2012 PMCID:3277540
Tantawy, MN, Jiang, R, Wang, F, Takahashi, K, Peterson, TE, Zemel, D, Hao, CM, Fujita, H, Harris, RC, Quarles, CC, Takahashi, T. Assessment of renal function in mice with unilateral ureteral obstruction using 99mTc-MAG3 dynamic scintigraphy. BMC Nephrol, 13, 168, 2012
Zhang, MZ, Wang, S, Yang, S, Yang, H, Fan, X, Takahashi, T, Harris, RC. Role of blood pressure and the renin-angiotensin system in development of diabetic nephropathy (DN) in eNOS-/- db/db mice. Am J Physiol Renal Physiol, 302(4), F433-8, 2012 PMCID:3277540
Beckham, JT, Wilmink, GJ, Opalenik, SR, Mackanos, MA, Abraham, AA, Takahashi, K, Contag, CH, Takahashi, T, Jansen, ED. Microarray analysis of cellular thermotolerance. Lasers Surg Med, 42(10), 752-65, 2010 PMCID:3277540
Fujita, H, Fujishima, H, Chida, S, Takahashi, K, Qi, Z, Kanetsuna, Y, Breyer, MD, Harris, RC, Yamada, Y, Takahashi, T. Reduction of Renal Superoxide Dismutase in Progressive Diabetic Nephropathy. J Am Soc Nephrol, 20(6), 1303-1313, 2009 PMCID:2689908
Sacco, F, Tinti, M, Palma, A, Ferrari, E, Nardozza, AP, Hooft van Huijsduijnen, R, Takahashi, T, Castagnoli, L, Cesareni, G. Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases. J Biol Chem, 2009
Tarcic, G, Boguslavsky, SK, Wakim, J, Kiuchi, T, Liu, A, Reinitz, F, Nathanson, D, Takahashi, T, Mischel, PS, Ng, T, Yarden, Y. An unbiased screen identifies DEP-1 tumor suppressor as a phosphatase controlling EGFR endocytosis. Curr Biol, 19(21), 1788-98, 2009
Beckham, JT, Wilmink, GJ, Mackanos, MA, Takahashi, K, Contag, CH, Takahashi, T, Jansen, ED. Role of HSP70 in cellular thermotolerance. Lasers Surg Med, 40(10), 704-15, 2008
Fang, WB, Ireton, RC, Zhuang, G, Takahashi, T, Reynolds, A, Chen, J. Overexpression of EPHA2 receptor destabilizes adherens junctions via a RhoA-dependent mechanism. J Cell Sci, 121(Pt 3), 358-68, 2008
Ito, H, Fujita, H, Takahashi, T. Diagnostic biomarkers of diabetic nephropathy. Expert Opin Med Diagn, 2(2), 161-9, 2008
Tsuboi, N, Utsunomiya, T, Roberts, RL, Ito, H, Takahashi, K, Noda, M, Takahashi, T. The tyrosine phosphatase CD148 interacts with the p85 regulatory subunit of phosphoinositide 3-kinase. Biochem J, 413(1), 193-200, 2008
Yamamoto, I, Horita, S, Takahashi, T, Kobayashi, A, Toki, D, Tanabe, K, Hattori, M, Teraoka, S, Aita, K, Nagata, M, Yamaguchi, Y. Caveolin-1 expression is a distinct feature of chronic rejection-induced transplant capillaropathy. Am J Transplant, 8(12), 2627-35, 2008
Breyer, MD, Tchekneva, E, Qi, Z, Takahashi, T, Fogo, AB, Harris, RC. Examining diabetic nephropathy through the lens of mouse genetics. Curr Diab Rep, 7(6), 459-66, 2007
Breyer, MD, Tchekneva, E, Qi, Z, Takahashi, T, Fogo, AB, Zhao, HJ, Harris, RC. Genetics of diabetic nephropathy: lessons from mice. Semin Nephrol, 27(2), 237-47, 2007
Faley, SL, Takahashi, K, Crooke, CE, Beckham, JT, Tomemori, T, Shappell, SB, Jansen, ED, Takahashi, T. Bioluminescence imaging of vascular endothelial growth factor promoter activity in murine mammary tumorigenesis. Mol Imaging, 6(5), 331-9, 2007
Kanetsuna, Y, Takahashi, K, Nagata, M, Gannon, MA, Breyer, MD, Harris, RC, Takahashi, T. Deficiency of endothelial nitric-oxide synthase confers susceptibility to diabetic nephropathy in nephropathy-resistant inbred mice. Am J Pathol, 170(5), 1473-84, 2007 PMCID:1854944
Yamamoto, I, Horita, S, Takahashi, T, Tanabe, K, Fuchinoue, S, Teraoka, S, Hattori, M, Yamaguchi, Y. Glomerular expression of plasmalemmal vesicle-associated protein-1 in patients with transplant glomerulopathy. Am J Transplant, 7(8), 1954-60, 2007
Chen, J, Boyle, S, Zhao, M, Su, W, Takahashi, K, Davis, L, Decaestecker, M, Takahashi, T, Breyer, MD, Hao, CM. Differential expression of the intermediate filament protein nestin during renal development and its localization in adult podocytes. J Am Soc Nephrol, 17(5), 1283-91, 2006
Kanetsuna, Y, Hirano, K, Nagata, M, Gannon, MA, Takahashi, K, Harris, RC, Breyer, MD, Takahashi, T. Characterization of diabetic nephropathy in a transgenic model of hypoinsulinemic diabetes. Am J Physiol Renal Physiol, 291(6), F1315-22, 2006
Takahashi, T, Morrow, JD, Wang, H, Dey, SK. Cyclooxygenase-2-derived prostaglandin E(2) directs oocyte maturation by differentially influencing multiple signaling pathways. J Biol Chem, 281(48), 37117-29, 2006 PMCID:1854944
Takahashi, T, Takahashi, K, Mernaugh, RL, Tsuboi, N, Liu, H, Daniel, TO. A monoclonal antibody against CD148, a receptor-like tyrosine phosphatase, inhibits endothelial-cell growth and angiogenesis. Blood, 108(4), 1234-42, 2006 PMCID:1895872
Wang, H, Xie, H, Guo, Y, Zhang, H, Takahashi, T, Kingsley, PJ, Marnett, LJ, Das, SK, Cravatt, BF, Dey, SK. Fatty acid amide hydrolase deficiency limits early pregnancy events. J Clin Invest, 116(8), 2122-31, 2006 PMCID:1523389
Zhao, HJ, Wang, S, Cheng, H, Zhang, MZ, Takahashi, T, Fogo, AB, Breyer, MD, Harris, RC. Endothelial nitric oxide synthase deficiency produces accelerated nephropathy in diabetic mice. J Am Soc Nephrol, 17(10), 2664-9, 2006
Anumanthan, G, Halder, SK, Osada, H, Takahashi, T, Massion, PP, Carbone, DP, Datta, PK. Restoration of TGF-beta signalling reduces tumorigenicity in human lung cancer cells. Br J Cancer, 93(10), 1157-67, 2005 PMCID:2361493
Beckham, Joshua T, Mackanos, Mark A, Crooke, Cornelia, Takahashi, Takamune, O''Connell-Rodwell, Caitlin, Contag, Christopher H, Jansen, E Duco. Assessment of cellular response to thermal laser injury through bioluminescence imaging of heat shock protein 70. Photochem Photobiol, 79(1), 76-85, 2004
Parker, M, Roberts, R, Enriquez, M, Zhao, X, Takahashi, T, Pat Cerretti, D, Daniel, T, Chen, J. Reverse endocytosis of transmembrane ephrin-B ligands via a clathrin-mediated
pathway. Biochem Biophys Res Commun, 323(1), 17-23, 2004
Xu, Y, Kashiwakura, I, Takahashi, TA. High sensitivity of megakaryocytic progenitor cells contained in placental/umbilical cord blood to the stresses during cryopreservation. Bone Marrow Transplant, 34(6), 537-43, 2004 PMCID:2361493
Grazia Lampugnani M, Zanetti A, Corada M, Takahashi T, Balconi G, Breviario F, Orsenigo F, Cattelino A, Kemler R, Daniel TO, Dejana E.
. Contact inhibition of VEGF-induced proliferation requires vascular endothelial cadherin, beta-catenin, and the phosphatase DEP-1/CD148.
. J Cell Biol., 26(161), 793-804, 2003
Takahashi, T, Takahashi, K, St John, PL, Fleming, PA, Tomemori, T, Watanabe, T, Abrahamson, DR, Drake, CJ, Shirasawa, T, Daniel, TO. A mutant receptor tyrosine phosphatase, CD148, causes defects in vascular development. Mol Cell Biol, 23(5), 1817-31, 2003 PMCID:151692
Usui J, Kurihara H, Shu Y, Tomari S, Kanemoto K, Koyama A, Sakai T, Takahashi T, Nagata M.
. Localization of intercellular adherens junction protein p120 catenin during podocyte differentiation.
. Anat Embryol (Berl). , 206(3), 175-84, 2003
Dikov, MM, Oyama, T, Cheng, P, Takahashi, T, Takahashi, K, Sepetavec, T, Edwards, B, Adachi, Y, Nadaf, S, Daniel, T, Gabrilovich, DI, Carbone, DP. Vascular endothelial growth factor effects on nuclear factor-kappaB activation
in hematopoietic progenitor cells. Cancer Res, 61(5), 2015-21, 2001
Takahashi, T, Takahashi, K, Gerety, S, Wang, H, Anderson, DJ, Daniel, TO. Temporally compartmentalized expression of ephrin-B2 during renal glomerular
development. J Am Soc Nephrol, 12(12), 2673-82, 2001
Daniel, TO, Stein, E, Huynh-Do, U, Takahashi, T. 4 signaling between endothelial progenitor cell. J Histochem Cytochem, 47(12), 1643C-1644, 1999
Takahashi T., Takahashi K. and Daniel TO. . High Efficiency & Low Toxicity Adenovirus-
assisted Endothelial Transfection.. Methods in Molecular Medicine, Vascular Disease: Molecular Biology and Gene Therapy Protocols., 304-314, 1999
Takahashi, T, Takahashi, K, Mernaugh, R, Drozdoff, V, Sipe, C, Schoecklmann, H, Robert, B, Abrahamson, DR, Daniel, TO. Endothelial localization of receptor tyrosine phosphatase, ECRTP/DEP-1, in
developing and mature renal vasculature. J Am Soc Nephrol, 10(10), 2135-45, 1999
Takahashi, T, Huynh-Do, U, Daniel, TO. Renal microvascular assembly and repair: power and promise of molecular definition. Kidney Int, 53(4), 826-35, 1998
Takahashi T, Shirasawa T, Miyake K, Yahagi Y, Matsumura O, Abe A, Natori Y, Yamabe H, Utsunomiya Y, Maruyama N, Mitarai T, Sakai O.
. Jak3 expression in glomerular epithelia of IgA nephropathy (IgA-N) patients.
. Clin Exp Immunol., 104(3), 517-24, 1996
Park SY, Saijo K, Takahashi T, Osawa M, Arase H, Hirayama N, Miyake K, Nakauchi H, Shirasawa T, Saito T.
. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice.
. Immunity., 3(6), 771-82, 1995
Takahashi T, Shirasawa T, Miyake K, Yahagi Y, Maruyama N, Kasahara N, Kawamura T, Matsumura O, Mitarai T, Sakai O.
. Protein tyrosine kinases expressed in glomeruli and cultured glomerular cells: Flt-1 and VEGF expression in renal mesangial cells.
. Biochem Biophys Res Commun., 209(1), 218-26, 1995
Takahashi T, Shirasawa T.
. Molecular cloning of rat JAK3, a novel member of the JAK family of protein tyrosine kinases.
. FEBS Lett., 342(2), 124-8, 1994
Postdoctoral position is available to study molecular mechanisms in angiogenesis or in kidney disease. Projects include: 1) Study to determine the role of tyrosine phosphatase in endothelial cells and angiogenesis. 2) Study to investigate the pathogenic mechanisms of kidney disease, with emphasis on diabetic nephropathy and endothelial injury.
Interested applicants should send C.V. to:
Takamune Takahashi, M.D., Ph.D.
Division of Nephrology and Hypertension
S-3223, Medical Center North,
Nashville, TN 37232