Keigi Fujiwara, PhD
Department of Cardiology, Division of Internal Medicine
Present Title & Affiliation
Primary Appointment
Professor, Department of Cardiology - Research, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX
Research Interests
I am a cell biologist interested in cell motility such as cell migration, cell division, intracellular organelle trafficking, and cell contraction. Our studies on the cytoskeleton of endothelial cells have led us to the field of endothelial mechanotransduction. Unique flow and cell stretch apparatuses are developed to study endothelial cell responses to mechanical forces. Through a series of in vitro cell and molecular biological studies, we were able to identify platelet endothelial cell adhesion molecule 1 (PECAM-1/CD31) to be a mechanosensor molecule of endothelial cells. The precise mechanism for mechanotransduction by PECAM-1 is being investigated. Our studies are also aimed at endothelial cell biology and physiology, especially on topics related to the cytoskeleton and cell adhesion and to cell signaling in the context of atherogenesis and endothelial dysfunction. In the past several years, I am collaborating with Dr. Jun-ichi Abe, Professor, UT MD Anderson Cancer Center, to study signaling cascades in endothelial cells that are exposed to disturbed flow. Identifying signaling cascades activated specifically by disturbed flow is an important step towards the discovery of new pharmacologic interventions for atherosclerosis and other cardiovascular diseases. Our studies are also focused on negative effects of cancer treatments on the cardiovascular system, which has become a critical issue for cancer patients and survivors. As a graduate student in the Biophysical Cytology Program at Penn headed by Dr. Shinya Inoue, I received arguably the best training on light microscopy. Throughout my scientific career, I have given numerous numbers of workshops, courses, and lectures on microscopy, especially fluorescence microscopy and live cell imaging techniques such as confocal and multi-photon microscopy, FRET, TIRF, intravital microscopy, polarization microscopy, and time lapse recording.
Education & Training
Degree-Granting Education
| 1974 | University of Pennsylvania, Phildelphia, PA, USA, PHD, Biology, Program in Biophysical Cytology |
| 1968 | International Christian University, Mitaka, JPN, BA, Natural Sciences; Division of Biology |
Postgraduate Training
| 1974-1977 | Research Fellowship, Harvard Medical School, Department of Anatomy, Boston, MA |
| 1973-1973 | Physiology Course, Marine Biological Laboratory, Wood Holes, MA |
Honors & Awards
| 1978 | Steps-Toward-Independence Fellowship, Marine Biological Laboratory |
| 1975 | Muscular Dystrophy Association Postdoctoral Fellowship, Muscular Dystrophy Association |
| 1962 | American Field Service (AFS) International Scholarship, American Field Service (AFS) |
Selected Publications
Peer-Reviewed Articles
- Smolock EM, Burke RM, Wang C, Thomas T, Batchu SN, Qiu X, Zettel M, Fujiwara K, Berk BC, Korshunov VA. Intima modifier locus 2 controls endothelial cell activation and vascular permeability. Physiol Genomics 46(17):624-33, 2014. e-Pub 2014. PMID: 24986958.
- Heo KS, Cushman HJ, Akaike M, Woo CH, Wang X, Qiu X, Fujiwara K, Abe J. ERK5 activation in macrophages promotes efferocytosis and inhibits atherosclerosis. Circulation 130(2):180-91, 2014. e-Pub 2014. PMID: 25001623.
- Heo KS, Chang E, Le NT, Cushman H, Yeh ET, Fujiwara K, Abe J. De-SUMOylation enzyme of sentrin/SUMO-specific protease 2 regulates disturbed flow-induced SUMOylation of ERK5 and p53 that leads to endothelial dysfunction and atherosclerosis. Circ Res 112(6):911-23, 2013. e-Pub 2013. PMID: 23381569.
- 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 33(2):321-9, 2013. e-Pub 2012. PMID: 23202365.
- 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 127(4):486-99, 2013. e-Pub 2012. PMID: 23243209.
- Kim GY, Nigro P, Fujiwara K, Abe J, Berk BC. p62 binding to protein kinase C ζ regulates tumor necrosis factor α-induced apoptotic pathway in endothelial cells. Arterioscler Thromb Vasc Biol 32(12):2974-80, 2012. e-Pub 2012. PMID: 23023376.
- 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 110(4):536-50, 2012. e-Pub 2012. PMID: 22267842.
- 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 110(4):560-8, 2012. e-Pub 2012. PMID: 22267843.
- 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 106(6):1023-39, 2011. e-Pub 2011. PMID: 22012077.
- 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. PKCζ mediates disturbed flow-induced endothelial apoptosis via p53 SUMOylation. J Cell Biol 193(5):867-84, 2011. PMID: 21624955.
- 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 117(8):2527-37, 2011. e-Pub 2010. PMID: 21131586.
- 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 116(11):1971-9, 2010. e-Pub 2010. PMID: 20538799.
- Shi F, Harman J, Fujiwara K, Sottile J. Collagen I matrix turnover is regulated by fibronectin polymerization. Am J Physiol Cell Physiol 298(5):C1265-75, 2010. e-Pub 2010. PMID: 20107040.
- Chiu YJ, McBeath E, Fujiwara K. Mechanotransduction in an extracted cell model: Fyn drives stretch- and flow-elicited PECAM-1 phosphorylation. J Cell Biol 182(4):753-63, 2008. e-Pub 2008. PMID: 18710921.
- Kusano K, Thomas TN, Fujiwara K. Phosphorylation and localization of protein-zero related (PZR) in cultured endothelial cells. Endothelium 15(3):127-36, 2008. PMID: 18568953.
- 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 73(4):813-22, 2007. e-Pub 2006. PMID: 17289004.
- 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 94(8):1041-9, 2004. e-Pub 2004. PMID: 15016733.
- 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 158(4):773-85, 2002. e-Pub 2002. PMID: 12177047.
- Hosokawa H, Ninomiya H, Kitamura Y, Fujiwara K, Masaki T. Vascular endothelial cells that express dystroglycan are involved in angiogenesis. J Cell Sci 115(Pt 7):1487-96, 2002. PMID: 11896196.
- 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 280(6):C1669-79, 2001. PMID: 11350763.
- Katoh K, Kano Y, Amano M, Onishi H, Kaibuchi K, Fujiwara K. Rho-kinase--mediated contraction of isolated stress fibers. J Cell Biol 153(3):569-84, 2001. PMID: 11331307.
- Konishi K, Kojima Si , Katoh T, Yazawa M, Kato K, Fujiwara K, Onishi H. Two new modes of smooth muscle myosin regulation by the interaction between the two regulatory light chains, and by the S2 domain. J Biochem 129(3):365-72, 2001. PMID: 11226875.
- 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 40(3):657-64, 2001. PMID: 11170382.
- 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 97(21):11203-8, 2000. PMID: 11016961.
- Kano Y, Katoh K, Fujiwara K. Lateral zone of cell-cell adhesion as the major fluid shear stress-related signal transduction site. Circ Res 86(4):425-33, 2000. PMID: 10700447.
- 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 92(3):704-8, 1995. PMID: 7846039.
- 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 91(9):3921-5, 1994. PMID: 8171013.
- Ito K, Masuda M, Fujiwara K, Sato H. Do astral microtubules play a role in metaphase chromosome positioning?. Biol Cell 82(2-3):95-102, 1994. PMID: 7606219.
- Jinguji Y, Fujiwara K. Stress fiber dependent axial organization of fibronectin fibrils in the basal lamina of the chick aorta and mesenteric artery. Endothelium(2):35-47, 1994.
- Sunada H, Masuda M, Fujiwara K. Preservation of differentiated phenotypes in cultured aortic endothelial cells by malotilate and phosphoascorbic acid. Eur J Cell Biol 60(1):48-56, 1993. PMID: 8462600.
- Iwata Y, Nakamura H, Fujiwara K, Shigekawa M. Altered membrane-dystrophin association in the cardiomyopathic hamster heart muscle. Biochem Biophys Res Commun 190(2):589-95, 1993. PMID: 8427601.
- Masuda M, Fujiwara K. Morphological responses of single endothelial cells exposed to physiological levels of fluid shear stress. Front Med Biol Eng 5(2):79-87, 1993. PMID: 8241033.
- 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 77(3):237-45, 1993. PMID: 8401287.
- Yamaguchi T, Hoshiai K, Okino H, Sakurai A, Hanai S, Masuda M, Fujiwara K. Shear stress distribution over confluently cultured endothelial cells studied by computational fluid mechanics. BED (Bioengin. Conf.)(24):167-170, 1993.
- Yamaguchi T, Masuda M, Hanai S, Fujiwara K. Do vascular endothelial cells sense a uniform shear stress? –A computational fluid mechanical study using models of cultured endothelial cells. Microcircul Ann 9:195-166, 1993.
- Onishi H, Maita T, Matsuda G, Fujiwara K. Interaction between the heavy and the regulatory light chains in smooth muscle myosin subfragment 1. Biochemistry 31(4):1201-10, 1992. PMID: 1734966.
- Sakurai A, Nakano A, Yamaguchi T, Masuda M, Fujiwara K. A computational fluid mechanical study of flow over cultured endothelial cells. BED (Adv. Bioeng.) 20:299-302, 1991.
- 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 265(31):19362-8, 1990. PMID: 1977747.
- 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 52(1):1-16, 1990. PMID: 2387301.
- Onishi H, Fujiwara K. The rigor configuration of smooth muscle heavy meromyosin trapped by a zero-length cross-linker. Biochemistry 29(12):3013-23, 1990. PMID: 2140049.
- McBeath E, Fujiwara K. Coalignment of microtubules, cytokeratin intermediate filaments, and collagen fibrils in a collagen-secreting cell system. Eur J Cell Biol 50(2):510-21, 1989. PMID: 2483378.
- Onishi H, Maita T, Matsuda G, Fujiwara K. Evidence for the association between two myosin heads in rigor acto-smooth muscle heavy meromyosin. Biochemistry 28(4):1898-904, 1989. PMID: 2524210.
- 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 28(4):1905-12, 1989. PMID: 2655699.
- 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 47(2):222-32, 1988. PMID: 3149586.
- Terasaki M, Chen LB, Fujiwara K. Microtubules and the endoplasmic reticulum are highly interdependent structures. J Cell Biol 103(4):1557-68, 1986. PMID: 3533956.
- White GE, Fujiwara K. Expression and intracellular distribution of stress fibers in aortic endothelium. J Cell Biol 103(1):63-70, 1986. PMID: 3722269.
- 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 123(3):440-53, 1986. PMID: 2424311.
- Heath E, Aire T, Fujiwara K. Microtubular mass defect of spermatozoa in the stallion. Am J Vet Res 46(5):1121-5, 1985. PMID: 3890632.
- Longtine JA, Pinkus GS, Fujiwara K, Corson JM. Immunohistochemical localization of smooth muscle myosin in normal human tissues. J Histochem Cytochem 33(3):179-84, 1985. PMID: 3882826.
- McBeath E, Fujiwara K. Improved fixation for immunofluorescence microscopy using light-activated 1,3,5-triazido-2,4,6-trinitrobenzene (TTB). J Cell Biol 99(6):2061-73, 1984. PMID: 6389569.
- 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 99(5):1582-9, 1984. PMID: 6208199.
- Larson DM, Fujiwara K, Alexander RW, Gimbrone MA. Heterogeneity of myosin antigenic expression in vascular smooth muscle in vivo. Lab Invest 50(4):401-7, 1984. PMID: 6368971.
- White GE, Gimbrone MA, Fujiwara K. Factors influencing the expression of stress fibers in vascular endothelial cells in situ. J Cell Biol 97(2):416-24, 1983. PMID: 6684121.
- Fay FS, Fujiwara K, Rees DD, Fogarty KE. Distribution of alpha-actinin in single isolated smooth muscle cells. J Cell Biol 96(3):783-95, 1983. PMID: 6403554.
- 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 79(23):7590-4, 1982. PMID: 6760199.
- 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 94(2):425-43, 1982. PMID: 7202010.
- Byers HR, Fujiwara K, Porter KR. Visualization of microtubules of cells in situ by indirect immunofluorescence. Proc Natl Acad Sci U S A 77(11):6657-61, 1980. PMID: 6935678.
- Tucker RW, Pardee AB, Fujiwara K. Centriole ciliation is related to quiescence and DNA synthesis in 3T3 cells. Cell 17(3):527-35, 1979. PMID: 476831.
- Mooseker MS, Pollard TD, Fujiwara K. Characterization and localization of myosin in the brush border of intestinal epithelial cells. J Cell Biol 79(2 Pt 1):444-53, 1978. PMID: 152766.
- 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 79(2 Pt 1):409-18, 1978. PMID: 309887.
- 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 79(2 Pt 1):419-26, 1978. PMID: 363728.
- Fujiwara K, Porter ME, Pollard TD. Alpha-actinin localization in the cleavage furrow during cytokinesis. J Cell Biol 79(1):268-75, 1978. PMID: 359574.
- Fujiwara K, Pollard TD. Simultaneous localization of myosin and tubulin in human tissue culture cells by double antibody staining. J Cell Biol 77(1):182-95, 1978. PMID: 350890.
- Wassarman PM, Fujiwara K. Immunofluorescent anti-tubulin staining of spindles during meiotic maturation of mouse oocytes in vitro. J Cell Sci 29:171-88, 1978. PMID: 75210.
- Schreiner GF, Fujiwara K, Pollard TD, Unanue ER. Redistribution of myosin accompanying capping of surface Ig. J Exp Med 145(5):1393-8, 1977. PMID: 323408.
- Fujiwara K, Pollard TD. Fluorescent antibody localization of myosin in the cytoplasm, cleavage furrow, and mitotic spindle of human cells. J Cell Biol 71(3):848-75, 1976. PMID: 62755.
- Tilney LG, Bryan J, Bush DJ, Fujiwara K, Mooseker MS, Murphy DB, Snyder DH. Microtubules: evidence for 13 protofilaments. J Cell Biol 59(2 Pt 1):267-75, 1973. PMID: 4805001.
- Le NT, Takei Y, Izawa-Ishizawa Y, Heo K-S, Lee H, Smrcka AV, Miller BL, Ko KA, Ture S, Morrell C, Fujiwara K, Akaike M, Abe J. Identification of activators of ERK5 transcriptional activity by high-throughput screening and the role of endothelial ERK5 in vasoprotective effects induced by statins and antimalarial agents. J Immunol 193:3803-3815. e-Pub 2014.
Invited Articles
- Xu S, Ha CH, Wang W, Xu X, Yin M, Jin FQ, Mastrangelo M, Koroleva M, Fujiwara K, Jin ZG.. PECAM1 regulates flow-mediated Gab1 tyrosine phosphorylation and signaling. Cellular Signaling 28:117-124, 2016.
- Heo KS, Le NT, Cushman HJ, Giancursio CJ, Chang E, Woo CH, Sullivan MA, Taunton J, Yeh ETH, Fujiwara K, Abe J.. Disturbed flow-activated p90RSK kinase accelerates atherosclerosis by inhibiting SENP2 function. J Clin Invest 125(3):1299-1310, 2015.
- Chatterjee S, Fujiwara K, Perez NG, Ushio-Fukai M, Fisher AB.. Mechanosignaling in the vasculature: emerging concepts in sensing, transduction and physiological responses. Am J Physiol Heart Circ Physiol 308:H1451–H1462, 2015.
- Katoh K, Kano Y, Fujiwara K. Isolation and in vitro contraction of stress fibers. Regulation and Effectors of Small GTPases 325:369-380, 2000.
- Pollard TD, Fujiwara K, Handin R, Weiss G. Contractile proteins in platelet activation and contraction. The Behavior of Blood and Its Components at Interfaces 283:218-236, 1977.
- Fujiwara K, Tilney LG. Substructural analysis of the microtubule and its polymorphic forms. The Biology of Cytoplasmic Microtubules 253:27-50, 1975.
- Mao Y, Luo W, Zhang L, Wu W, Yuan L, Xu H, Fujiwara K, Abe J, Wang XL, and Shen YH.. STING-IRF3 triggers endothelial inflammation in response to free fatty acid-induced mitochondrial damage. Arterioscler Thromb Vasc Biol.
- KO KA, Fujiwara K, Abe J.. En face preparation of mouse blood vessels. J Vis Exp.
Book Chapters
- Pollard TD, Fujiwara K, Niederman R, Maupin-Szamier P. Evidence for the role of cytoplasmic actin and myosin in cellular structure and motility. In: Cell Motility. Cold Speing Harbor PRess: New York, 689-724, 1976.
- Sato H, Ohnuki Y, Fujiwara K. Immunofluorescent anti-tubulin staining of spindle microtubules; and critique for the techniques. In: Cell Motility. Cold Spring Harbor Press: New York, 419-433, 1976.
Grant & Contract Support
| Title: | Mechanism of PECAM-1 tyrosine phosphorylation |
| Funding Source: | American Heart Association |
| Role: | Principal Investigator |
| Title: | Fluid shear stress signal transduction in endothelium |
| Funding Source: | NIH/NHLBI |
| Role: | Co-Principal Investigator |
| Title: | Single molecule force spectroscopy analysis of PECAM-1 mechanotransduction |
| Funding Source: | NIH/NHLBI |
| Role: | Co-Principal Investigator |
| Title: | Implantable cell-embedded biosensor for heart failure |
| Funding Source: | Clinical Translational Science Institute (CTSI) Grant |
| Role: | Co-Principal Investigator |