Keigi Fujiwara
| Title | Research Professor |
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| Institution | School of Medicine and Dentistry |
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| Department | Medicine in the Aab Cardiovascular Research Institute |
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| Address | Aab Cardiovascular Research Institute
211 Bailey Road
West Henrietta NY 14586
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| 1962 |
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| 1963 | American Field Service Internatiolan Scholarship | | 1978 |
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| Steps-Toward-Independence Fellowship, Marine Biological Laboratory |
Research Overview
Dr. Fujiwara's major research is on mechanosignaling by vascular endothelial cells. Mechanical forces such as fluid flow and stretch trigger unique responses in endothelial cells, indicating that they are capable of sensing mechanical forces. However, the molecular mechanism responsible for this interesting ability of the cells is largely unknown. The recent studies by his research group have indicated that that an endothelial cell adhesion molecule, PECAM-1 (also called CD31) and the actin cytoskeleton are involved in this mechanism. When endothelial cells are exposed to a physiological levels of fluid shear stress, PECAM-1 is rapidly phosphorylated at two tyrosine residues, and this tyrosine phosphorylation appears to be one of the earliest protein modification events one can detect in these cells. Interestingly, PECAM-1 can be also tyrosine phosphorylated by tugging force applied directly to the molecule on the cell surface, suggesting that this molecule is mechanoresponsive. At present, following specific questions are being investigated: (1) what happens to PECAM-1 when mechanical force is applied to it?, (2) how is PECAM-1 tyrosine phosphorylated by mechanical force?, (3) what signaling events are activated by PECAM-1 phosphorylation?, and (4) what role does the actin cytoskeleton play in PECAM-1 signaling? To answer these questions, the laboratory uses techniques of molecular and cell biology, structural analyses, and animal models including PECAM-1 KO mice.
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Le NT, Heo KS, Takei Y, Lee H, Woo CH, Chang E, McClain C, Hurley C, Wang X, Li F, Xu H, Morrell C, Sullivan MA, Cohen MS, Serafimova IM, Taunton J, Fujiwara K, Abe J. A Crucial Role for p90RSK-Mediated Reduction of ERK5 Transcriptional Activity in Endothelial Dysfunction and Atherosclerosis. Circulation. 2013 Jan 29; 127(4):486-99.
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Heo KS, Chang E, Takei Y, Le NT, Woo CH, Sullivan MA, Morrell C, Fujiwara K, Abe J. Phosphorylation of Protein Inhibitor of Activated STAT1 (PIAS1) by MAPK-Activated Protein Kinase-2 Inhibits Endothelial Inflammation via Increasing Both PIAS1 Transrepression and SUMO E3 Ligase Activity. Arterioscler Thromb Vasc Biol. 2013 Feb; 33(2):321-9.
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Heo KS, Fujiwara K, Abe J. Glucagon-like Peptide-1 and its cardiovascular effects. Curr Atheroscler Rep. 2012 Oct; 14(5):422-8.
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Kim GY, Nigro P, Fujiwara K, Abe J, Berk BC. p62 Binding to Protein Kinase C ? Regulates Tumor Necrosis Factor a-Induced Apoptotic Pathway in Endothelial Cells. Arterioscler Thromb Vasc Biol. 2012 Dec; 32(12):2974-80.
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Le NT, Corsetti JP, Dehoff-Sparks JL, Sparks CE, Fujiwara K, Abe J. Reactive Oxygen Species, SUMOylation, and Endothelial Inflammation. Int J Inflam. 2012; 2012:678190.
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Wang XQ, Nigro P, World C, Fujiwara K, Yan C, Berk BC. Thioredoxin interacting protein promotes endothelial cell inflammation in response to disturbed flow by increasing leukocyte adhesion and repressing kruppel-like factor 2. Circ Res. 2012 Feb 17; 110(4):560-8.
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Le NT, Takei Y, Shishido T, Woo CH, Chang E, Heo KS, Lee H, Lu Y, Morrell C, Oikawa M, McClain C, Wang X, Tournier C, Molina CA, Taunton J, Yan C, Fujiwara K, Patterson C, Yang J, Abe J. p90RSK Targets the ERK5-CHIP Ubiquitin E3 Ligase Activity in Diabetic Hearts and Promotes Cardiac Apoptosis and Dysfunction. Circ Res. 2012 Feb 17; 110(4):536-50.
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Heo KS, Fujiwara K, Abe J. Disturbed-flow-mediated vascular reactive oxygen species induce endothelial dysfunction. Circ J. 2011 Nov 25; 75(12):2722-30.
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Miller CL, Cai Y, Oikawa M, Thomas T, Dostmann WR, Zaccolo M, Fujiwara K, Yan C. Cyclic nucleotide phosphodiesterase 1A: a key regulator of cardiac fibroblast activation and extracellular matrix remodeling in the heart. Basic Res Cardiol. 2011 Nov; 106(6):1023-39.
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Heo KS, Lee H, Nigro P, Thomas T, Le NT, Chang E, McClain C, Reinhart-King CA, King MR, Berk BC, Fujiwara K, Woo CH, Abe J. PKC? mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation. J Cell Biol. 2011 May 30; 193(5):867-84.
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Chang E, Heo KS, Woo CH, Lee H, Le NT, Thomas TN, Fujiwara K, Abe J. MK2 SUMOylation regulates actin filament remodeling and subsequent migration in endothelial cells by inhibiting MK2 kinase and HSP27 phosphorylation. Blood. 2011 Feb 24; 117(8):2527-37.
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Nigro P, Abe J, Woo CH, Satoh K, McClain C, O'Dell MR, Lee H, Lim JH, Li JD, Heo KS, Fujiwara K, Berk BC. PKCzeta decreases eNOS protein stability via inhibitory phosphorylation of ERK5. Blood. 2010 Sep 16; 116(11):1971-9.
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Shi F, Harman J, Fujiwara K, Sottile J. Collagen I matrix turnover is regulated by fibronectin polymerization. Am J Physiol Cell Physiol. 2010 May; 298(5):C1265-75.
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Chiu YJ, McBeath E, Fujiwara K. Mechanotransduction in an extracted cell model: Fyn drives stretch- and flow-elicited PECAM-1 phosphorylation. J Cell Biol. 2008 Aug 25; 182(4):753-63.
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Kusano K, Thomas TN, Fujiwara K. Phosphorylation and localization of protein-zero related (PZR) in cultured endothelial cells. Endothelium. 2008 May-Jun; 15(3):127-36.
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Reinhart-King CA, Fujiwara K, Berk BC. Physiologic stress-mediated signaling in the endothelium. Methods Enzymol. 2008; 443:25-44.
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Berk BC, Fujiwara K, Lehoux S. ECM remodeling in hypertensive heart disease. J Clin Invest. 2007 Mar; 117(3):568-75.
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Shi F, Chiu YJ, Cho Y, Bullard TA, Sokabe M, Fujiwara K. Down-regulation of ERK but not MEK phosphorylation in cultured endothelial cells by repeated changes in cyclic stretch. Cardiovasc Res. 2007 Mar 1; 73(4):813-22.
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Miano JM, Long X, Fujiwara K. Serum response factor: master regulator of the actin cytoskeleton and contractile apparatus. Am J Physiol Cell Physiol. 2007 Jan; 292(1):C70-81.
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Fujiwara K. Platelet endothelial cell adhesion molecule-1 and mechanotransduction in vascular endothelial cells. J Intern Med. 2006 Apr; 259(4):373-80.
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van Nieuw Amerongen GP, Natarajan K, Yin G, Hoefen RJ, Osawa M, Haendeler J, Ridley AJ, Fujiwara K, van Hinsbergh VW, Berk BC. GIT1 mediates thrombin signaling in endothelial cells: role in turnover of RhoA-type focal adhesions. Circ Res. 2004 Apr 30; 94(8):1041-9.
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Chiu YJ, Kusano K, Thomas TN, Fujiwara K. Endothelial cell-cell adhesion and mechanosignal transduction. Endothelium. 2004 Jan-Feb; 11(1):59-73.
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Fujiwara K. Mechanical stresses keep endothelial cells healthy: beneficial effects of a physiological level of cyclic stretch on endothelial barrier function. Am J Physiol Lung Cell Mol Physiol. 2003 Oct; 285(4):L782-4.
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Osawa M, Masuda M, Kusano K, Fujiwara K. Evidence for a role of platelet endothelial cell adhesion molecule-1 in endothelial cell mechanosignal transduction: is it a mechanoresponsive molecule? J Cell Biol. 2002 Aug 19; 158(4):773-85.
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Hosokawa H, Ninomiya H, Kitamura Y, Fujiwara K, Masaki T. Vascular endothelial cells that express dystroglycan are involved in angiogenesis. J Cell Sci. 2002 Apr 1; 115(Pt 7):1487-96.
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Katoh K, Kano Y, Amano M, Kaibuchi K, Fujiwara K. Stress fiber organization regulated by MLCK and Rho-kinase in cultured human fibroblasts. Am J Physiol Cell Physiol. 2001 Jun; 280(6):C1669-79.
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Katoh K, Kano Y, Amano M, Onishi H, Kaibuchi K, Fujiwara K. Rho-kinase--mediated contraction of isolated stress fibers. J Cell Biol. 2001 Apr 30; 153(3):569-84.
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Fujiwara K, Masuda M, Osawa M, Kano Y, Katoh K. Is PECAM-1 a mechanoresponsive molecule? Cell Struct Funct. 2001 Feb; 26(1):11-7.
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Kojima S, Konishi K, Katoh K, Fujiwara K, Martinez HM, Morales MF, Onishi H. Functional roles of ionic and hydrophobic surface loops in smooth muscle myosin: their interactions with actin. Biochemistry. 2001 Jan 23; 40(3):657-64.
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Onishi H, Konishi K, Fujiwara K, Hayakawa K, Tanokura M, Martinez HM, Morales MF. On the tryptophan residue of smooth muscle myosin that responds to binding of nucleotide. Proc Natl Acad Sci U S A. 2000 Oct 10; 97(21):11203-8.
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Kojima S, Fujiwara K, Onishi H. SH1 (cysteine 717) of smooth muscle myosin: its role in motor function. Biochemistry. 1999 Sep 7; 38(36):11670-6.
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Hosokawa H, Ninomiya H, Sawamura T, Sugimoto Y, Ichikawa A, Fujiwara K, Masaki T. Neuron-specific expression of cationic amino acid transporter 3 in the adult rat brain. Brain Res. 1999 Aug 14; 838(1-2):158-65.
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Katoh K, Kano Y, Masuda M, Onishi H, Fujiwara K. Isolation and contraction of the stress fiber. Mol Biol Cell. 1998 Jul; 9(7):1919-38.
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Onishi H, Kojima S, Katoh K, Fujiwara K, Martinez HM, Morales MF. Functional transitions in myosin: formation of a critical salt-bridge and transmission of effect to the sensitive tryptophan. Proc Natl Acad Sci U S A. 1998 Jun 9; 95(12):6653-8.
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Fujiwara K, Masuda M, Osawa M, Katoh K, Kano Y, Harada N, Lopes RB. Response of vascular endothelial cells to fluid flow. Biol Bull. 1998 Jun; 194(3):384-5; discussion 385-6.
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Ochi H, Kume N, Nishi E, Moriwaki H, Masuda M, Fujiwara K, Kita T. Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 induced by lysophosphatidylcholine in cultured endothelial cells. Biochem Biophys Res Commun. 1998 Feb 24; 243(3):862-8.
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Masuda M, Osawa M, Shigematsu H, Harada N, Fujiwara K. Platelet endothelial cell adhesion molecule-1 is a major SH-PTP2 binding protein in vascular endothelial cells. FEBS Lett. 1997 May 26; 408(3):331-6.
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Onishi H, Morales MF, Kojima S, Katoh K, Fujiwara K. Functional transitions in myosin: role of highly conserved Gly and Glu residues in the active site. Biochemistry. 1997 Apr 1; 36(13):3767-72.
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Redhead C, Sullivan SK, Koseki C, Fujiwara K, Edwards JC. Subcellular distribution and targeting of the intracellular chloride channel p64. Mol Biol Cell. 1997 Apr; 8(4):691-704.
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Osawa M, Masuda M, Harada N, Lopes RB, Fujiwara K. Tyrosine phosphorylation of platelet endothelial cell adhesion molecule-1 (PECAM-1, CD31) in mechanically stimulated vascular endothelial cells. Eur J Cell Biol. 1997 Mar; 72(3):229-37.
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Kano Y, Katoh K, Masuda M, Fujiwara K. Macromolecular composition of stress fiber-plasma membrane attachment sites in endothelial cells in situ. Circ Res. 1996 Nov; 79(5):1000-6.
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Katoh K, Kano Y, Masuda M, Fujiwara K. Mutually exclusive distribution of the focal adhesion associated proteins and the erythrocyte membrane skeleton proteins in the human fibroblast plasma membrane undercoat. Cell Struct Funct. 1996 Feb; 21(1):27-39.
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Onishi H, Morales MF, Katoh K, Fujiwara K. The putative actin-binding role of hydrophobic residues Trp546 and Phe547 in chicken gizzard heavy meromyosin. Proc Natl Acad Sci U S A. 1995 Dec 19; 92(26):11965-9.
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Harada N, Masuda M, Fujiwara K. Fluid flow and osmotic stress induce tyrosine phosphorylation of an endothelial cell 128 kDa surface glycoprotein. Biochem Biophys Res Commun. 1995 Sep 5; 214(1):69-74.
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Onishi H, Maéda K, Maéda Y, Inoue A, Fujiwara K. Functional chicken gizzard heavy meromyosin expression in and purification from baculovirus-infected insect cells. Proc Natl Acad Sci U S A. 1995 Jan 31; 92(3):704-8.
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Katoh K, Masuda M, Kano Y, Jinguji Y, Fujiwara K. Focal adhesion proteins associated with apical stress fibers of human fibroblasts. Cell Motil Cytoskeleton. 1995; 31(3):177-95.
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Ito K, Masuda M, Fujiwara K, Hayashi H, Sato H. Metaphase and anaphase in the artificially induced monopolar spindle. Proc Natl Acad Sci U S A. 1994 Apr 26; 91(9):3921-5.
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Ito K, Masuda M, Fujiwara K, Sato H. Do astral microtubules play a role in metaphase chromosome positioning? Biol Cell. 1994; 82(2-3):95-102.
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Sunada H, Masuda M, Fujiwara K. Preservation of differentiated phenotypes in cultured aortic endothelial cells by malotilate and phosphoascorbic acid. Eur J Cell Biol. 1993 Feb; 60(1):48-56.
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Iwata Y, Nakamura H, Fujiwara K, Shigekawa M. Altered membrane-dystrophin association in the cardiomyopathic hamster heart muscle. Biochem Biophys Res Commun. 1993 Jan 29; 190(2):589-95.
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Masuda M, Fujiwara K. Morphological responses of single endothelial cells exposed to physiological levels of fluid shear stress. Front Med Biol Eng. 1993; 5(2):79-87.
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Masuda M, Fujiwara K. The biased lamellipodium development and microtubule organizing center position in vascular endothelial cells migrating under the influence of fluid flow. Biol Cell. 1993; 77(3):237-45.
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Onishi H, Maita T, Matsuda G, Fujiwara K. Interaction between the heavy and the regulatory light chains in smooth muscle myosin subfragment 1. Biochemistry. 1992 Feb 4; 31(4):1201-10.
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Onishi H, Maita T, Matsuda G, Fujiwara K. Lys-65 and Glu-168 are the residues for carbodiimide-catalyzed cross-linking between the two heads of rigor smooth muscle heavy meromyosin. J Biol Chem. 1990 Nov 5; 265(31):19362-8.
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McBeath E, Fujiwara K. Microtubule detachment from the microtubule-organizing center as a key event in the complete turnover of microtubules in cells. Eur J Cell Biol. 1990 Jun; 52(1):1-16.
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Onishi H, Fujiwara K. The rigor configuration of smooth muscle heavy meromyosin trapped by a zero-length cross-linker. Biochemistry. 1990 Mar 27; 29(12):3013-23.
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McBeath E, Fujiwara K. Coalignment of microtubules, cytokeratin intermediate filaments, and collagen fibrils in a collagen-secreting cell system. Eur J Cell Biol. 1989 Dec; 50(2):510-21.
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Onishi H, Maita T, Matsuda G, Fujiwara K. Evidence for the association between two myosin heads in rigor acto-smooth muscle heavy meromyosin. Biochemistry. 1989 Feb 21; 28(4):1898-904.
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Onishi H, Maita T, Matsuda G, Fujiwara K. Carbodiimide-catalyzed cross-linking sites in the heads of gizzard heavy meromyosin attached to F-actin. Biochemistry. 1989 Feb 21; 28(4):1905-12.
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Nishikawa S, Fujiwara K, Kitamura H. Formation of the tooth enamel rod pattern and the cytoskeletal organization in secretory ameloblasts of the rat incisor. Eur J Cell Biol. 1988 Dec; 47(2):222-32.
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Terasaki M, Chen LB, Fujiwara K. Microtubules and the endoplasmic reticulum are highly interdependent structures. J Cell Biol. 1986 Oct; 103(4):1557-68.
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White GE, Fujiwara K. Expression and intracellular distribution of stress fibers in aortic endothelium. J Cell Biol. 1986 Jul; 103(1):63-70.
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Pinkus GS, Warhol MJ, O'Connor EM, Etheridge CL, Fujiwara K. Immunohistochemical localization of smooth muscle myosin in human spleen, lymph node, and other lymphoid tissues. Unique staining patterns in splenic white pulp and sinuses, lymphoid follicles, and certain vasculature, with ultrastructural correlations. Am J Pathol. 1986 Jun; 123(3):440-53.
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Heath E, Aire T, Fujiwara K. Microtubular mass defect of spermatozoa in the stallion. Am J Vet Res. 1985 May; 46(5):1121-5.
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Longtine JA, Pinkus GS, Fujiwara K, Corson JM. Immunohistochemical localization of smooth muscle myosin in normal human tissues. J Histochem Cytochem. 1985 Mar; 33(3):179-84.
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McBeath E, Fujiwara K. Improved fixation for immunofluorescence microscopy using light-activated 1,3,5-triazido-2,4,6-trinitrobenzene (TTB). J Cell Biol. 1984 Dec; 99(6):2061-73.
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Larson DM, Fujiwara K, Alexander RW, Gimbrone MA. Myosin in cultured vascular smooth muscle cells: immunofluorescence and immunochemical studies of alterations in antigenic expression. J Cell Biol. 1984 Nov; 99(5):1582-9.
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Larson DM, Fujiwara K, Alexander RW, Gimbrone MA. Heterogeneity of myosin antigenic expression in vascular smooth muscle in vivo. Lab Invest. 1984 Apr; 50(4):401-7.
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White GE, Gimbrone MA, Fujiwara K. Factors influencing the expression of stress fibers in vascular endothelial cells in situ. J Cell Biol. 1983 Aug; 97(2):416-24.
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Fay FS, Fujiwara K, Rees DD, Fogarty KE. Distribution of alpha-actinin in single isolated smooth muscle cells. J Cell Biol. 1983 Mar; 96(3):783-95.
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Matus A, Ackermann M, Pehling G, Byers HR, Fujiwara K. High actin concentrations in brain dendritic spines and postsynaptic densities. Proc Natl Acad Sci U S A. 1982 Dec; 79(23):7590-4.
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Hirokawa N, Tilney LG, Fujiwara K, Heuser JE. Organization of actin, myosin, and intermediate filaments in the brush border of intestinal epithelial cells. J Cell Biol. 1982 Aug; 94(2):425-43.
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Tomasek JJ, Hay ED, Fujiwara K. Collagen modulates cell shape and cytoskeleton of embryonic corneal and fibroma fibroblasts: distribution of actin, alpha-actinin, and myosin. Dev Biol. 1982 Jul; 92(1):107-22.
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Byers HR, Fujiwara K. Stress fibers in cells in situ: immunofluorescence visualization with antiactin, antimyosin, and anti-alpha-actinin. J Cell Biol. 1982 Jun; 93(3):804-11.
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Meyrick B, Fujiwara K, Reid L. Smooth muscle myosin in precursor and mature smooth muscle cells in normal pulmonary arteries and the effect of hypoxia. Exp Lung Res. 1981 Nov; 2(4):303-13.
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Hoover RL, Fujiwara K, Klausner RD, Bhalla DK, Tucker R, Karnovsky MJ. Effects of free fatty acids on the organization of cytoskeletal elements in lymphocytes. Mol Cell Biol. 1981 Oct; 1(10):939-48.
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Byers HR, Fujiwara K, Porter KR. Visualization of microtubules of cells in situ by indirect immunofluorescence. Proc Natl Acad Sci U S A. 1980 Nov; 77(11):6657-61.
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Tucker RW, Pardee AB, Fujiwara K. Centriole ciliation is related to quiescence and DNA synthesis in 3T3 cells. Cell. 1979 Jul; 17(3):527-35.
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Braun J, Fujiwara K, Pollard TD, Unanue ER. Two distinct mechanisms for redistribution of lymphocyte surface macromolecules. II. Contrasting effects of local anesthetics and a calcium ionophore. J Cell Biol. 1978 Nov; 79(2 Pt 1):419-26.
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Mooseker MS, Pollard TD, Fujiwara K. Characterization and localization of myosin in the brush border of intestinal epithelial cells. J Cell Biol. 1978 Nov; 79(2 Pt 1):444-53.
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Braun J, Fujiwara K, Pollard TD, Unanue ER. Two distinct mechanisms for redistribution of lymphocyte surface macromolecules. I. Relationship to cytoplasmic myosin. J Cell Biol. 1978 Nov; 79(2 Pt 1):409-18.
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Fujiwara K, Porter ME, Pollard TD. Alpha-actinin localization in the cleavage furrow during cytokinesis. J Cell Biol. 1978 Oct; 79(1):268-75.
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Fujiwara K, Pollard TD. Simultaneous localization of myosin and tubulin in human tissue culture cells by double antibody staining. J Cell Biol. 1978 Apr; 77(1):182-95.
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Wassarman PM, Fujiwara K. Immunofluorescent anti-tubulin staining of spindles during meiotic maturation of mouse oocytes in vitro. J Cell Sci. 1978 Feb; 29:171-88.
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Schreiner GF, Fujiwara K, Pollard TD, Unanue ER. Redistribution of myosin accompanying capping of surface Ig. J Exp Med. 1977 May 1; 145(5):1393-8.
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Fujiwara K, Pollard TD. Fluorescent antibody localization of myosin in the cytoplasm, cleavage furrow, and mitotic spindle of human cells. J Cell Biol. 1976 Dec; 71(3):848-75.
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Tilney LG, Bryan J, Bush DJ, Fujiwara K, Mooseker MS, Murphy DB, Snyder DH. Microtubules: evidence for 13 protofilaments. J Cell Biol. 1973 Nov; 59(2 Pt 1):267-75.
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