Cell Adhesion Mechanisms in Vascular Disease &Thrombosis

Summary

Principal Investigator: MARK HOWARD GINSBERG
Abstract: Support is requested to continue a program designed to advance understanding of molecular mechanisms of vascular disease and to promote development of new diagnostic, therapeutic, and preventive strategies through the collaborative efforts of a group of experienced scientists focused oh the unifying theme of cell adhesion. This interdisciplinary program will span disciplines of biochemistry, cell biology, ex-vivo and in vivo studies to assess the effects of blood flow on adhesion and signaling, and analysis of genetically-modified mice and zebrafish. In Project 1, Dr. Ginsberg will study the activation of integrins and resulting thrombus formation by platelets and arrest of leukocytes. Specific studies will address the activation of integrins in purified systems, the role of RIAM, the interactions and structure of integrin transmembrane domains, and the in vivo and ex vivo consequences of perturbing integrin activation in platelets and leukocytes. In Project 2, Dr.Shattil will continue to develop and utilize strategies to visualize interactions of proteins with platelet integrin alpha lIb beta 3 in living cells and he will analyze the signaling mechanisms of alpha V integrins in vivo in zebrafish. In Project 3, Dr. Ruggeri will build on advances in the structure of von Willebrand Factor (VWF) and platelet GPIb. Specifically, he will seek to better understand the biomechanical properties of the bonds between GPIb and VWF in flowing blood, the effects of thrombin on the GPlb/VWF interaction, and the biological role of a newly-discovered immunoglobulin modulator of thrombosis. Mouse Genetics Core Unit A, led by Dr. Petrich, will provide expertise, genomic constructs, genotyping, well characterized murine embryonic stem cells, and blastocyst injections for the purpose of genetic manipulation of mice. This core will be used to generate talin knock-ins that selectively perturb integrin activation and will provide conditional transgenic animals. Microfluidics Core Unit B, led by Dr. Groisman, a physicist, will develop and provide high throughput multichannel microfluidic flow systems to analyze platelet and leukocyte adhesion to conventional and patterned substrates under controlled shear stress. Administrative Core Unit C will continue to provide administrative support. Altogether, this interdisciplinary program will enable remarkable synergies amongst a group of accomplished investigators who will test new hypotheses and utilize and develop cutting edge methodologies to advance understanding of cell adhesion events in vascular biology and thrombosis.
Funding Period: 2005-02-15 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc C-terminal COOH of integrin β1 is necessary for β1 association with the kindlin-2 adapter protein
    Paul Fitzpatrick
    From the Department of Medicine, University of California San Diego, La Jolla, California 92093 0726
    J Biol Chem 289:11183-93. 2014
  2. pmc Role for ADAP in shear flow-induced platelet mechanotransduction
    Ana Kasirer-Friede
    Department of Medicine, University of California San Diego, La Jolla, CA 92093 0726, USA
    Blood 115:2274-82. 2010
  3. pmc Recreation of the terminal events in physiological integrin activation
    Feng Ye
    Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    J Cell Biol 188:157-73. 2010
  4. pmc Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage
    Nancy A Turner
    Department of Bioengineering, Rice University, 6500 Main St, Houston, TX 77030, USA
    Blood 114:5102-11. 2009
  5. pmc Thrombopoietin in normal and neoplastic stem cell development
    Kenneth Kaushansky
    University of California San Diego Medical Center, San Diego, CA 92103 8811, USA
    Best Pract Res Clin Haematol 22:495-9. 2009
  6. pmc Distinct spatio-temporal Ca2+ signaling elicited by integrin alpha2beta1 and glycoprotein VI under flow
    Mario Mazzucato
    Department of Laboratory Medicine, Centro di Riferimento Oncologico CRO National Cancer Institute, Istituti di Ricovero e Cura a Carattere Scientifico IRCCS, Aviano PN, Italy
    Blood 114:2793-801. 2009
  7. pmc The structure of an integrin/talin complex reveals the basis of inside-out signal transduction
    Nicholas J Anthis
    Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
    EMBO J 28:3623-32. 2009
  8. pmc An easy to assemble microfluidic perfusion device with a magnetic clamp
    Eugene Tkachenko
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0726, La Jolla, CA 92093, USA
    Lab Chip 9:1085-95. 2009
  9. pmc Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration
    Cai Huang
    Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599, USA
    Nat Cell Biol 11:624-30. 2009
  10. pmc Glycosyltransferase function in core 2-type protein O glycosylation
    Erica L Stone
    Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA
    Mol Cell Biol 29:3770-82. 2009

Research Grants

Detail Information

Publications66

  1. pmc C-terminal COOH of integrin β1 is necessary for β1 association with the kindlin-2 adapter protein
    Paul Fitzpatrick
    From the Department of Medicine, University of California San Diego, La Jolla, California 92093 0726
    J Biol Chem 289:11183-93. 2014
    ..Thus, by employing zebrafish as an in situ physiological tool to correlate protein structure and function, we have discovered an unexpected association chemistry between an integrin and a key adapter involved in integrin signaling. ..
  2. pmc Role for ADAP in shear flow-induced platelet mechanotransduction
    Ana Kasirer-Friede
    Department of Medicine, University of California San Diego, La Jolla, CA 92093 0726, USA
    Blood 115:2274-82. 2010
    ..These results establish that ADAP is an essential component of alphaIIbbeta3-mediated platelet mechanotransduction that promotes F-actin assembly and enables platelet spreading and thrombus stabilization under fluid shear stress...
  3. pmc Recreation of the terminal events in physiological integrin activation
    Feng Ye
    Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    J Cell Biol 188:157-73. 2010
    ....
  4. pmc Endothelial cell ADAMTS-13 and VWF: production, release, and VWF string cleavage
    Nancy A Turner
    Department of Bioengineering, Rice University, 6500 Main St, Houston, TX 77030, USA
    Blood 114:5102-11. 2009
    ..Constitutive ADAMTS-13 released from endothelial cells may contribute to the maintenance of cell surfaces free of hyperadhesive VWF multimeric strings...
  5. pmc Thrombopoietin in normal and neoplastic stem cell development
    Kenneth Kaushansky
    University of California San Diego Medical Center, San Diego, CA 92103 8811, USA
    Best Pract Res Clin Haematol 22:495-9. 2009
    ..The c-MPL receptor may also play an important role in the development of human myeloproliferative disorders, essential thrombocythemia, myelofibrosis and polycythemia vera, cooperating with the dysregulated Janus kinase JAK2V(617)F...
  6. pmc Distinct spatio-temporal Ca2+ signaling elicited by integrin alpha2beta1 and glycoprotein VI under flow
    Mario Mazzucato
    Department of Laboratory Medicine, Centro di Riferimento Oncologico CRO National Cancer Institute, Istituti di Ricovero e Cura a Carattere Scientifico IRCCS, Aviano PN, Italy
    Blood 114:2793-801. 2009
    ..Our results delineate a GPVI-independent signaling role of alpha2beta1 in response to collagen stimulation...
  7. pmc The structure of an integrin/talin complex reveals the basis of inside-out signal transduction
    Nicholas J Anthis
    Department of Biochemistry, University of Oxford, South Parks Road, Oxford OX1 3QU, UK
    EMBO J 28:3623-32. 2009
    ..These results show key structural features that explain the ability of talin to mediate inside-out TM signalling...
  8. pmc An easy to assemble microfluidic perfusion device with a magnetic clamp
    Eugene Tkachenko
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0726, La Jolla, CA 92093, USA
    Lab Chip 9:1085-95. 2009
    ..The magnetic clamp can be closed with minimal mechanical perturbation to cells on the substrate and used with a variety of microfluidic chips for experiments with adherent and non-adherent cells...
  9. pmc Talin phosphorylation by Cdk5 regulates Smurf1-mediated talin head ubiquitylation and cell migration
    Cai Huang
    Department of Cell and Developmental Biology, University of North Carolina, Chapel Hill, NC 27599, USA
    Nat Cell Biol 11:624-30. 2009
    ....
  10. pmc Glycosyltransferase function in core 2-type protein O glycosylation
    Erica L Stone
    Howard Hughes Medical Institute, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, California 92093, USA
    Mol Cell Biol 29:3770-82. 2009
    ..Although the absence of C2GnT and C4GnT activities is tolerable in vivo, core 2 O glycosylation exerts a significant influence on O-glycan biosynthesis and is important in multiple physiological processes...
  11. pmc Antithrombotic effects of targeting alphaIIbbeta3 signaling in platelets
    Ararat J Ablooglu
    Department of Medicine, University of California San Diego, La Jolla, CA 92093 0726, USA
    Blood 113:3585-92. 2009
    ..Thus, deletion of beta3 RGT disrupts c-Src-mediated alphaIIbbeta3 signaling and confers protection from arterial thrombosis. Consequently, targeting alphaIIbbeta3 signaling may represent a feasible antithrombotic strategy...
  12. pmc Group IVA cytosolic phospholipase A2 (cPLA2alpha) and integrin alphaIIbbeta3 reinforce each other's functions during alphaIIbbeta3 signaling in platelets
    Nicolas Prevost
    Departments of Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093 0726, USA
    Blood 113:447-57. 2009
    ..This provides a plausible explanation for the role of alphaIIbbeta3 in TxA(2) formation and in the defective hemostatic function of mouse or human platelets deficient in cPLA(2)alpha...
  13. pmc Platelet adhesion under flow
    Zaverio M Ruggeri
    Roon Research Center for Arteriosclerosis and Thrombosis, Division of Blood Cell and Vascular Biology, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037, USA
    Microcirculation 16:58-83. 2009
    ..The adaptation of platelet-adhesive functions to the effects of blood flow is the main focus of this review...
  14. pmc RIAM activates integrins by linking talin to ras GTPase membrane-targeting sequences
    Ho Sup Lee
    Department of Medicine, University of California San Diego, La Jolla, California 92093 0726, USA
    J Biol Chem 284:5119-27. 2009
    ..These data establish the mechanism whereby MRL proteins interact with both talin and Ras GTPases to activate integrins...
  15. pmc Dependence of proliferative vascular smooth muscle cells on CD98hc (4F2hc, SLC3A2)
    Per Fogelstrand
    Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    J Exp Med 206:2397-406. 2009
    ....
  16. pmc Integrin alphaV is necessary for gastrulation movements that regulate vertebrate body asymmetry
    Ararat J Ablooglu
    Department of Medicine, University of California San Diego, La Jolla, CA 92093 0726, USA
    Development 137:3449-58. 2010
    ....
  17. pmc Ubiquitination and degradation of the thrombopoietin receptor c-Mpl
    Sebastian J Saur
    Department of Medicine, University of California San Diego, La Jolla, CA, USA
    Blood 115:1254-63. 2010
    ....
  18. pmc Rap1 and its effector KRIT1/CCM1 regulate beta-catenin signaling
    Angela J Glading
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
    Dis Model Mech 3:73-83. 2010
    ..Thus, KRIT1 regulates beta-catenin signaling, and Krit1(+/-) mice are more susceptible to beta-catenin-driven intestinal adenomas...
  19. pmc Integrin αII b tail distal of GFFKR participates in inside-out αII b β3 activation
    A Li
    Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, China
    J Thromb Haemost 12:1145-55. 2014
    ..Research has focused on the conserved GFFKR motif in integrin αII b tails, integrin β cytoplasmic tails and the binding partners of β tails. However, the roles of αII b tail distal of GFFKR motif are unexplored...
  20. pmc The mechanism of kindlin-mediated activation of integrin αIIbβ3
    Feng Ye
    Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    Curr Biol 23:2288-95. 2013
    ..Thus, in contrast to talins, kindlins have little primary effect on integrin αIIbβ3 affinity for monovalent ligands and increase multivalent ligand binding by promoting the clustering of talin-activated integrins...
  21. pmc Molecular imaging of inflammation and platelet adhesion in advanced atherosclerosis effects of antioxidant therapy with NADPH oxidase inhibition
    Yani Liu
    Division of Cardiovascular Medicine, Oregon Health and Science University, Portland, OR 97239, USA
    Circ Cardiovasc Imaging 6:74-82. 2013
    ..We used molecular imaging to test whether inhibition of NADPH oxidase with apocynin would reduce endothelial inflammatory activation and endothelial-platelet interactions, thereby interrupting progression to high-risk plaque phenotype...
  22. pmc Basic amino-acid side chains regulate transmembrane integrin signalling
    Chungho Kim
    Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA
    Nature 481:209-13. 2012
    ..Thus, widely occurring snorkelling residues in TMDs can help maintain TMD topography and membrane-embedding, thereby regulating transmembrane signalling...
  23. pmc CD98 at the crossroads of adaptive immunity and cancer
    Joseph M Cantor
    Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
    J Cell Sci 125:1373-82. 2012
    ..We suggest that the CD98 amplification of integrin signaling in adaptive immunity provides survival benefits to vertebrates, which, in turn, bear the price of increased susceptibility to cancer...
  24. pmc Reconstruction of integrin activation
    Feng Ye
    Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
    Blood 119:26-33. 2012
    ..Here, we review recent progress in reconstructing integrin signaling and the insights that we have gained through these experiments...
  25. pmc Platelet mimetic particles for targeting thrombi in flowing blood
    Nishit Doshi
    Department of Chemical Engineering, University of California, Santa Barbara, CA
    Adv Mater 24:3864-9. 2012
    ..These synthetic platelets have therapeutic and diagnostic applications for platelet associated disorders...
  26. pmc Microwell devices with finger-like channels for long-term imaging of HIV-1 expression kinetics in primary human lymphocytes
    Brandon S Razooky
    Department of Chemistry and Biochemistry, University of California, San Diego, CA 92023, USA
    Lab Chip 12:4305-12. 2012
    ..The proposed devices offer a simple, robust approach to long-term single-cell studies of environmentally sensitive primary lymphocytes...
  27. pmc Subcellular localization of talin is regulated by inter-domain interactions
    Asoka Banno
    Department of Medicine, University of California, San Diego, La Jolla, California 92093 0726, USA
    J Biol Chem 287:13799-812. 2012
    ..Thus, we have structurally defined specific inter-domain interactions between THD and the talin rod domain that regulate the subcellular localization of talin...
  28. pmc Kindlin-2 regulates podocyte adhesion and fibronectin matrix deposition through interactions with phosphoinositides and integrins
    Hong Qu
    Department of Pathology, University of Pittsburgh, Pittsburgh, PA 15261, USA
    J Cell Sci 124:879-91. 2011
    ..Our results reveal important functions of kindlin-2 in the regulation of podocyte-matrix adhesion and matrix deposition and shed new light on the mechanism whereby kindlin-2 functions in these processes...
  29. pmc Talin-dependent integrin activation is required for fibrin clot retraction by platelets
    Jacob R Haling
    Department of Medicine, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
    Blood 117:1719-22. 2011
    ....
  30. pmc Measurements of elastic moduli of silicone gel substrates with a microfluidic device
    Edgar Gutierrez
    Department of Physics, University of California San Diego, La Jolla, California, United States of America
    PLoS ONE 6:e25534. 2011
    ..This work can lead to broader use of silicone gels in the cell biology laboratory and to improved repeatability and accuracy of cell traction force microscopy and rigidity sensing experiments...
  31. pmc High refractive index silicone gels for simultaneous total internal reflection fluorescence and traction force microscopy of adherent cells
    Edgar Gutierrez
    Department of Physics, University of California San Diego, La Jolla, California, United States of America
    PLoS ONE 6:e23807. 2011
    ..Here we apply high-refractive-index silicone gels to perform TIRF microscopy on substrates with a wide range of physiological elastic moduli and simultaneously measure traction forces exerted by cells on the substrate...
  32. pmc Core2 1-6-N-glucosaminyltransferase-I is crucial for the formation of atherosclerotic lesions in apolipoprotein E-deficient mice
    Huan Wang
    Department of Medicine, University of Minnesota, 420 Delaware St SE, MMC508, Minneapolis, MN 55455, USA
    Arterioscler Thromb Vasc Biol 29:180-7. 2009
    ..The objective of this study was to determine the role of C2GlcNAcT-I in the recruitment of Ly-6C(hi) monocytes to atherosclerotic lesions and in lesion formation in mice...
  33. pmc Core2 1-6-N-glucosaminyltransferase-I deficiency protects injured arteries from neointima formation in ApoE-deficient mice
    Huan Wang
    Department of Medicine, University of Minnesota, Minneapolis, MN 55455, USA
    Arterioscler Thromb Vasc Biol 29:1053-9. 2009
    ....
  34. pmc ADAP is required for normal alphaIIbbeta3 activation by VWF/GP Ib-IX-V and other agonists
    Ana Kasirer-Friede
    Department of Medicine, University of California San Diego, La Jolla 92093 0726, USA
    Blood 109:1018-25. 2007
    ..These studies establish ADAP as a component of inside-out signaling pathways that couple GP Ib-IX-V and other platelet agonist receptors to alphaIIbbeta3 activation...
  35. pmc The role of von Willebrand factor in thrombus formation
    Zaverio M Ruggeri
    The Scripps Research Institute, La Jolla, California, USA
    Thromb Res 120:S5-9. 2007
    ..This VWF-mediated process may be a key determinant of platelet accumulation in stenotic arteries leading to acute thrombotic occlusion...
  36. pmc Syk, c-Src, the alphavbeta3 integrin, and ITAM immunoreceptors, in concert, regulate osteoclastic bone resorption
    Wei Zou
    Department of Pathology and Immunology, Washington University School of Medicine, St Louis, MO 63110, USA
    J Cell Biol 176:877-88. 2007
    ..Thus, in conjunction with ITAM-bearing proteins, Syk, c-Src, and alpha v beta3 represent an essential signaling complex in the bone-resorbing osteoclast, and, therefore, each is a candidate therapeutic target...
  37. ncbi CD98hc (SLC3A2) interaction with the integrin beta subunit cytoplasmic domain mediates adhesive signaling
    Gerald W Prager
    Department of Medicine, University of California San Diego, La Jolla, California 92093, USA
    J Biol Chem 282:24477-84. 2007
    ..These studies also provide new insights into how CD98hc may cooperate with other cytoplasmic domain binding proteins to modulate integrin functions and into the evolution of integrin signaling...
  38. pmc KRIT-1/CCM1 is a Rap1 effector that regulates endothelial cell cell junctions
    Angela Glading
    Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    J Cell Biol 179:247-54. 2007
    ..Thus, Rap1 increases KRIT-1 targeting to endothelial cell-cell junctions where it suppresses stress fibers and stabilizes junctional integrity...
  39. pmc Antiplatelet drug therapy moderates immune-mediated liver disease and inhibits viral clearance in mice infected with a replication-deficient adenovirus
    Matteo Iannacone
    Department of Molecular and Experimental Medicine, Scripps Research Institute, 10550 North Torrey Pines Rd, La Jolla, CA 92037, USA
    Clin Vaccine Immunol 14:1532-5. 2007
    ....
  40. ncbi An experimentally derived database of candidate Ras-interacting proteins
    Lawrence E Goldfinger
    Division of Rheumatology, Department of Medicine, University of California, San Diego, La Jolla, California 92093, USA
    J Proteome Res 6:1806-11. 2007
    ..R-Ras and Rap1A each associated with various signaling molecules, many of which are membrane-associated. Thus, we have established the first database of potential Ras interactors in mammalian cells...
  41. ncbi Tumor-suppressive effects of pannexin 1 in C6 glioma cells
    Charles P K Lai
    Departments of Cellular and Physiological Sciences and Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada
    Cancer Res 67:1545-54. 2007
    ..Altogether, we conclude that the loss of pannexin expression may participate in the development of C6 gliomas, whereas restoration of Panx1 plays a tumor-suppressive role...
  42. ncbi PEA-15 inhibits tumor cell invasion by binding to extracellular signal-regulated kinase 1/2
    Angela Glading
    Department of Medicine, University of California San Diego, The Scripps Research Institute, 9500 Gilman Drive, La Jolla, CA 92093, USA
    Cancer Res 67:1536-44. 2007
    ..These results reveal that PEA-15 regulates cancer cell invasion via its ability to bind ERK1/2 and indicate that nuclear entry of ERK1/2 is important in tumor behavior...
  43. pmc The antithrombotic potential of selective blockade of talin-dependent integrin alpha IIb beta 3 (platelet GPIIb-IIIa) activation
    Brian G Petrich
    Department of Medicine, UCSD School of Medicine, La Jolla, California 92093 0726, USA
    J Clin Invest 117:2250-9. 2007
    ..Furthermore, they suggest that modulation of beta(3) integrin-talin interactions may provide an attractive target for antithrombotics and result in a reduced risk of pathological bleeding...
  44. ncbi Altered von Willebrand factor subunit proteolysis and multimer processing associated with the Cys2362Phe mutation in the B2 domain
    Alessandra Casonato
    Dept of Medical and Surgical Sciences, Via Ospedale Civile 105, Padova, Italy
    Thromb Haemost 97:527-33. 2007
    ..Our findings indicate that a proper conformation of the B2 domain, which depends on critical Cys residues, may be required for the normal proteolytic processing of vWF multimers...
  45. ncbi Distinct antithrombotic consequences of platelet glycoprotein Ibalpha and VI deficiency in a mouse model of arterial thrombosis
    S Konstantinides
    Department of Molecular and Experimental Medicine, Division of Experimental Hemostasis and Thrombosis, The Roon Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute, La Jolla, CA, USA
    J Thromb Haemost 4:2014-21. 2006
    ..Collagen and von Willebrand factor (VWF) are considered essential to initiate platelet deposition at sites of vascular injury, but their respective roles remain to be elucidated...
  46. pmc Mechanism of platelet adhesion to von Willebrand factor and microparticle formation under high shear stress
    Armin J Reininger
    Department of Transfusion Medicine and Hemostaseology, University Clinic Munich, Ziemssenstr 1, 80336 Munich, Germany
    Blood 107:3537-45. 2006
    ....
  47. pmc Size regulation of von Willebrand factor-mediated platelet thrombi by ADAMTS13 in flowing blood
    Roberta Donadelli
    Department of Molecular and Experimental Medicine, Division of Experimental Hemostasis and Thrombosis, Roon Center for Arteriosclerosis and Thrombosis, The Scripps Research Institute MEM 175, 10550 North Torrey Pines Rd, La Jolla, CA 92037, USA
    Blood 107:1943-50. 2006
    ..ADAMTS13, therefore, may regulate thrombus size preferentially when the cohesion between platelets depends on VWF binding induced by pathologically elevated shear stress...
  48. pmc The chronic myeloproliferative disorders and mutation of JAK2: Dameshek's 54 year old speculation comes of age
    Kenneth Kaushansky
    Department of Medicine, Division of Hematology Oncology, University of California, San Diego, 402 Dickinson Street, Suite 380, CA 92103 8811, USA
    Best Pract Res Clin Haematol 20:5-12. 2007
    ....
  49. pmc Talin is required for integrin-mediated platelet function in hemostasis and thrombosis
    Brian G Petrich
    Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    J Exp Med 204:3103-11. 2007
    ..These data establish that platelet talin plays a crucial role in hemostasis and provide the first proof that talin is required for the activation and function of mammalian alpha2beta1 and alphaIIbbeta3 integrins in vivo...
  50. pmc Transcriptional regulation of bone marrow thrombopoietin by platelet proteins
    Bryan McIntosh
    Department of Medicine, University of California San Diego, San Diego, CA 92103 8811, USA
    Exp Hematol 36:799-806. 2008
    ..9-kb region between 250-bp upstream of the transcriptional initiation site and the middle of the second intron are able to mediate the transcriptional repression...
  51. pmc CD98hc facilitates B cell proliferation and adaptive humoral immunity
    Joseph Cantor
    Department of Medicine, University of California San Diego, La Jolla, USA
    Nat Immunol 10:412-9. 2009
    ..Thus, CD98hc supports integrin-dependent rapid proliferation of B cells. We propose that the advantage of adaptive immunity favored the appearance of CD98hc in vertebrates...
  52. pmc Regulation of cardiovascular development and integrity by the heart of glass-cerebral cavernous malformation protein pathway
    Benjamin Kleaveland
    Department of Medicine and Cardiovascular Institute, University of Pennsylvania, 421 Curie Blvd, Philadelphia, Pennsylvania 19104, USA
    Nat Med 15:169-76. 2009
    ..This study identifies HEG1-CCM protein signaling as a crucial regulator of heart and vessel formation and integrity...
  53. pmc Localized alpha4 integrin phosphorylation directs shear stress-induced endothelial cell alignment
    Lawrence E Goldfinger
    Sol Sherry Thrombosis Research Center and Department of Anatomy and Cell Biology, Temple University School of Medicine, 3400 N Broad Street, OMS 415, Philadelphia, PA 19140, USA
    Circ Res 103:177-85. 2008
    ..We thereby show that shear-induced PKA-dependent alpha4 integrin phosphorylation at the downstream edge of endothelial cells promotes localized Rac1 activation, which in turn directs cytoskeletal alignment in response to shear stress...
  54. pmc Integrin activation
    Asoka Banno
    Department of Medicine, University of California, San Diego, 9500 Gilman Drive, MC 0726, San Diego, CA 92093 0726, USA
    Biochem Soc Trans 36:229-34. 2008
    ..The central finding was that this Rap1-induced formation of an 'integrin activation complex' leads to the unmasking of the integrin-binding site on talin, resulting in integrin activation...
  55. pmc Platelets prevent IFN-alpha/beta-induced lethal hemorrhage promoting CTL-dependent clearance of lymphocytic choriomeningitis virus
    Matteo Iannacone
    Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA
    Proc Natl Acad Sci U S A 105:629-34. 2008
    ....
  56. pmc Roles of focal adhesion kinase (FAK) in megakaryopoiesis and platelet function: studies using a megakaryocyte lineage specific FAK knockout
    Ian S Hitchcock
    Department of Medicine, University of California San Diego, La Jolla 92093, USA
    Blood 111:596-604. 2008
    ..These studies establish clear roles for FAK in megakaryocyte growth and platelet function, setting the stage for manipulation of this component of the Tpo signaling apparatus for therapeutic benefit...
  57. pmc UV-C irradiation disrupts platelet surface disulfide bonds and activates the platelet integrin alphaIIbbeta3
    Robin Verhaar
    Department of Blood Cell Research, Sanquin Research, Amsterdam, The Netherlands
    Blood 112:4935-9. 2008
    ..Thus, UV-C appears to activate alphaIIbbeta3 not by affecting intracellular signal transduction, but by reduction of disulfide bonds regulating integrin conformation...
  58. pmc Integrin-mediated protein kinase A activation at the leading edge of migrating cells
    Chinten J Lim
    Department of Medicine, University of California San Diego, La Jolla, CA 92093 0726, USA
    Mol Biol Cell 19:4930-41. 2008
    ..In sum, we have visualized compartment-specific PKA activation in migrating cells and used it to reveal that adhesion-mediated localized activation of PKA is an early step in directional cell migration...
  59. pmc YRRL motifs in the cytoplasmic domain of the thrombopoietin receptor regulate receptor internalization and degradation
    Ian S Hitchcock
    Department of Medicine, University of California San Diego, La Jolla, CA 92093, USA
    Blood 112:2222-31. 2008
    ..Our data establishes that c-Mpl cytoplasmic YRRL motifs are responsible for both Tpo-mediated internalization via interactions with AP2 and lysosomal targeting after endocytosis...
  60. pmc The GPIIb/IIIa (integrin alphaIIbbeta3) odyssey: a technology-driven saga of a receptor with twists, turns, and even a bend
    Barry S Coller
    Laboratory of Blood and Vascular Biology, The Rockefeller University, New York, NY, USA
    Blood 112:3011-25. 2008
    ....
  61. pmc Microfluidic devices for studies of shear-dependent platelet adhesion
    Edgar Gutierrez
    Department of Physics, University of California San Diego, La Jolla, CA 92093, USA
    Lab Chip 8:1486-95. 2008
    ..Because of small sample volumes required, the devices could be employed in research with genetically-modified model organisms and for adhesion tests in clinical settings with blood from neonates...
  62. pmc Mammalian glycosylation in immunity
    Jamey D Marth
    Department of Cellular and Molecular Medicine, The Howard Hughes Medical Institute, University of California San Diego, La Jolla, California 92093, USA
    Nat Rev Immunol 8:874-87. 2008
    ..This Review focuses on the emerging immunological roles of the mammalian glycome...
  63. pmc Historical review: megakaryopoiesis and thrombopoiesis
    Kenneth Kaushansky
    Department of Medicine, University of California, San Diego, CA 92103 8811, USA
    Blood 111:981-6. 2008
    ....
  64. pmc RLIP76 (RalBP1) is an R-Ras effector that mediates adhesion-dependent Rac activation and cell migration
    Lawrence E Goldfinger
    Division of Rheumatology, Department of Medicine, University of California, San Diego, La Jolla, CA 92093, USA
    J Cell Biol 174:877-88. 2006
    ..Thus, we identify a novel R-Ras effector, RLIP76, which links R-Ras to adhesion-induced Rac activation through a GTPase cascade that mediates cell spreading and migration...

Research Grants30

  1. RAGE and Mechanisms of Vascular Dysfunction
    Shi Fang Yan; Fiscal Year: 2013
    ..Using novel and state-of-the-art techniques, floxed mice and molecular approaches to gene regulation, we are well-positioned to lead the study of RAGE in the next cycle of this Program. ..
  2. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..
  3. AMPK Endothelial Cell Dysfunction and the Metabolic Syndrome (PROGRAM PROJECT)
    Neil B Ruderman; Fiscal Year: 2013
    ..The proposed studies should both yield novel insights into the biological bases for the premature atherosclerosis and impaired angiogenesis associated with this entity and suggest new therapeutic targets for their prevention...
  4. Immune-Based Interventions Against Infectious Diseases
    Alan L Rothman; Fiscal Year: 2013
    ..3. Recruit promising junior investigators and provide mentoring by established NIH-funded researchers. 4. Support a multidisciplinary research program led by junior investigators in translational infectious diseases immunology. ..
  5. Endothelial Injury and Repair: CardioPulmonary Vascular Biology COBRE
    SHARON IRENE SMITH ROUNDS; Fiscal Year: 2013
    ..abstract_text> ..
  6. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  7. Digitalis-Induced Signaling by Cardiac Na+/K+-ATPase
    Amir Askari; Fiscal Year: 2013
    ..abstract_text> ..
  8. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..