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Integrin Interactions
Published by Anonymous on 2007/9/27 (1876 reads)
1: Cardiovasc Hematol Agents Med Chem. 2007 Jan;5(1):29-42.


Structure-activity relationship studies on ADAM protein-integrin interactions.

Lu X, Lu D, Scully MF, Kakkar VV.

Thrombosis Research Institute, Manresa Road, London, SW3 6LR, UK. xlu@tri-london.ac.uk

The ADAM (a disintegrin and metalloprotease) family of proteins possess multi-domain structures composed of a signal peptide, a prodomain, a metalloprotease domain, a disintegrin-like domain, a cysteine rich domain, an epidermal growth factor-like domain, a transmembrane domain and cytoplasmic tail. The disintegrin-like domain shares sequence similarity with the soluble venom disintegrins, a family of proteins which are potent inhibitors of integrin-mediated platelet aggregation and cell adhesion. Several ADAMs have been reported to interact with integrins, and the disintegrin-like domain may be crucial part in this respect. A description of structure-activity relationship of ADAM proteins interacting with integrin is outlined in this review. The review highlights recent reports on potential integrin family for ADAMs and how ADAMs selectively modulate interaction for integrin mediated cell function. Lastly, it describes progress in understanding the structural features and functional roles of the ADAMs in normal and pathological conditions and how this insight may assist the development of new therapeutic approaches.

Publication Types:
Review

PMID: 17266546 [PubMed - indexed for MEDLINE]

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2: Arterioscler Thromb Vasc Biol. 2006 Sep;26(9):1966-75. Epub 2006 Jun 15.


Integrin-matrix interactions in the cerebral microvasculature.

del Zoppo GJ, Milner R.

Department of Molecular and Experimental Medicine, The Scripps Research Institute, 10550 North Torrey Pines Road, MEM 132, La Jolla, CA 92037, USA. grgdlzop@scripps.edu

The integrity of all organ systems requires faithful interaction between its component cells and the extracellular matrix (ECM). In the central nervous system (CNS), matrix adhesion receptors are uniquely expressed by the cells comprising the microvascular compartment, and by neurons and their supporting glial cells. Cells within the cerebral microvasculature express both the integrin and dystroglycan families of matrix adhesion receptors. However, the functional significance of these receptors is only now being explored. Capillaries of the cerebral microvasculature consist of the luminal endothelium, which is separated from circumferential astrocyte end-feet by the intervening ECM of the basal lamina. Endothelial cells and astrocytes cooperate to generate and maintain the basal lamina and the unique barrier functions of the endothelium. Integrins and the dystroglycan complex are found on the matrix-proximate faces of both endothelial cells and astrocyte end-feet. Pericytes rest against the basal lamina. In the extravascular compartment, select integrins are expressed on neurons, microglial cells, and oligodendroglia. Significant alterations in both cellular adhesion receptors and their ligands occur under the conditions of focal cerebral ischemia, multiple sclerosis (MS) and the modeled condition experimental autoimmune encephalomyelitis (EAE), certain tumors of the CNS, and arteriovenous malformations (AVMs). The changes in matrix adhesion receptor expression in these conditions support their functional significance in the normal state. We propose that matrix adhesion receptors are essential for the maintenance of the integrity of the blood-brain permeability barrier, and that modulation of these receptors contribute to alterations in the barrier during brain injury. This review examines current information about cell adhesion receptor expression within the cerebral microvasculature and surrounding tissue, and their potential roles during the vascular responses to local injury.

Publication Types:
Research Support, N.I.H., Extramural
Review

PMID: 16778120 [PubMed - indexed for MEDLINE]

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3: Cancer Lett. 2006 Oct 8;242(1):11-9. Epub 2006 Jan 31.


Integrin-mediated cell-matrix interactions for prosurvival and antiapoptotic signaling after genotoxic injury.

Cordes N.

OncoRay-Radiation Research in Oncology, Medical Faculty Carl Gustav Carus, University of Technology Dresden,Fetscherstrasse 74/PF 86, 01307 Dresden, Germany. nils.cordes@oncoray.de

Interactions of cells with their microenvironment modify the cellular sensitivity of normal and tumor cells for radiation- and drug-induced genotoxic injury. The preexistent or acquired cellular resistance against such agents aggravates anticancer therapies and, therefore, complicates the recovery of patients. Recently, integrin-mediated adhesion was shown to improve cell survival of both normal and cancer cells following DNA damage. Here, I will discuss the role of integrins and integrin-mediated signaling cascades in the survival or death response upon genotoxic stress. Detailed knowledge of the responsible molecular processes might provide implications for putative therapies targeting integrins or integrin-associated molecules to achieve an optimization of anticancer treatments.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 16448744 [PubMed - indexed for MEDLINE]

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4: Curr Pharm Des. 2005;11(7):837-47.


ADAM-Integrin Interactions: potential integrin regulated ectodomain shedding activity.

Bridges LC, Bowditch RD.

Department of Biochemistry and Molecular Biology, The University of Oklahoma Health Sciences Center, Oklahoma City 73190, USA.

ADAMs (a disintegrin and metalloprotease) are a family of cell surface proteins related to the Class III snake venom metalloproteases (SVMP). ADAMs are members of the Metazincin family which includes the matrix matalloproteases and the ADAMTS proteins. Unlike their snake venom relatives, ADAMs are expressed as transmembrane cell surface proteins. The domain structure of ADAMs suggests that these proteins posses both proteolytic and adhesive functions. Several members of the ADAM protein family have been shown to be involved in ectodomain shedding of many important cell surface proteins resulting in the release of biologically active soluble factors. The carboxyl-terminal domains, especially the disintegrin-like domain of ADAMs, have been demonstrated to support cell adhesion. The disintegrin-like domains of many ADAMs are capable of acting as integrin ligands. Integrins known to interact with ADAM disintegrin-like domains include alpha4beta1, alpha4beta7, alpha5beta1, alpha6beta1, alpha9beta1, alphavbeta3, and alphavbeta5. This integrin mediated interaction of the disintegrin-like domains with the cell surface suggests that ADAMs may function as cellular counter receptors. In this review we discuss the individual functions ascribed to members of the ADAM family especially those related to integrin interactions and the potential for integrin mediated regulation of ectodomain shedding.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 15777238 [PubMed - indexed for MEDLINE]

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5: Cell Mol Life Sci. 2005 May;62(10):1081-99.


Integrin-actin interactions.

Wiesner S, Legate KR, Fässler R.

Department of Molecular Medicine, Max-Planck-Institut of Biochemistry, Martinsried, Germany. wiesner@biochem.mpg.de

The integrin family of extracellular matrix receptors regulates many aspects of cell life, in particular cell adhesion and migration. These two processes depend on organization of the actin cytoskeleton into adhesive and protrusive organelles in response to extracellular signals. Integrins are important switch points for the spatiotemporal control of actin-based motility in higher eukaryotes. Ligands of integrin cytoplasmic tails are central elements of signalling pathways involving small GTPases as well as protein and lipid kinases in the regulation of Factin crosslinking, actin treadmilling and de novo nucleation of actin filaments. We present an overview of common pathways and discuss recent evidence for their differential use by individual integrin receptors.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 15761669 [PubMed - indexed for MEDLINE]

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6: Hamostaseologie. 2005 Feb;25(1):33-8.


Integrin-mediated leukocyte adhesive interactions: regulation by haemostatic factors.

Chavakis T, Preissner KT.

Medizinische Klinik I, Universitätsklinikum Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. triantafyllos.chavakis@med.uni-heidelberg.de

Leukocyte recruitment to sites of inflammation, infection or vascular injury is a complex event that is orchestrated by a tightly coordinated sequence of interactions between leukocytes and cells of the vessel wall, especially endothelial cells. These interactions are controlled by the expression and activation of various adhesion receptors and protease systems. This review will focus on novel aspects of the regulation of integrin-dependent leukocyte adhesion by haemostatic factors. Here, so-called non-haemostatic properties of endogenous proteins such as high molecular weight kininogen, urokinase receptor, urokinase, as well as plasminogen and its cleavage product angiostatin in leukocyte adhesion and transmigration will be summarized. The crosstalk between haemostatic factors and inflammatory reactions may contribute to a better understanding of inflammatory vascular disorders and to the development of novel therapeutical concepts.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 15711718 [PubMed - indexed for MEDLINE]

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7: Glia. 2005 Mar;49(4):467-79.


Erratum in:
Glia. 2005 Jul;51(1):80. Ffrench-Constant, Charles [corrected to ffrench-Constant, Charles].

Integrin-growth factor interactions as regulators of oligodendroglial development and function.

Baron W, Colognato H, ffrench-Constant C.

Department of Membrane Cell Biology, Faculty of Medical Sciences, University of Groningen, Groningen, The Netherlands. w.baron@med.rug.nl

Central nervous system (CNS) development requires mechanisms for the regulation of cell number. Although growth factors are essential determinants of the proliferation and apoptosis that determine final numbers, the long-range nature of signals from diffusible growth factors makes them insufficient for the provision of the precise and localized signals required. Integration of integrin and growth factor receptor signaling in controlling cell behavior has been an important theme of research over the past several years. The focus of this review is on the mechanisms by which integrin-growth factor interactions regulate the development of oligodendrocytes and provide a mechanism for controlling, both in space and in time, oligodendrocyte numbers in the developing CNS.

Publication Types:
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 15578662 [PubMed - indexed for MEDLINE]

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8: Trends Biochem Sci. 2004 Sep;29(9):504-12.


P marks the spot: site-specific integrin phosphorylation regulates molecular interactions.

Fagerholm SC, Hilden TJ, Gahmberg CG.

Division of Biochemistry, Faculty of Biosciences, PB 56 (Viikinkaari 5), 00014 University of Helsinki, Finland. susanna.fagerholm@helsinki.fi

Integrins are heterodimeric adhesion receptors at the cell membrane that function as two-way signaling devices. The short intracellular tails of integrins are devoid of catalytic activity, but are nevertheless important for adhesion and signaling, presumably, through interactions with cytoplasmic molecules. Recently, the structure of the intracellular tails has been investigated using NMR, giving important new insight into how integrins might be regulated, but many questions remain unanswered. Signaling by many cell-surface receptors involves protein phosphorylation; over the past few years, phosphorylation of the integrin tails at specific sites has started to emerge as a dynamic mechanism that regulates molecular interactions between integrins and cytoplasmic molecules. This phosphorylation might give rise to signaling specificity and fine-tuning of the integrin-mediated responses.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 15337124 [PubMed - indexed for MEDLINE]

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9: Biochem Soc Trans. 2004 Jun;32(Pt3):426-30.


Lipid rafts: microenvironments for integrin-growth factor interactions in neural development.

Decker L, Baron W, Ffrench-Constant C.

Department of Pathology, Cambridge Centre for Brain Repair, University of Cambridge, Tennis Court Road, Cambridge CB2 1QP, UK.

The development of a complex multicellular organ such as the nervous system requires precise regulation of cell migration, proliferation and survival. This regulation in turn requires the integration of long-range signals, such as growth factors, with short-range cues that define the precise location and cellular neighbours for any given cell. This short review examines one integrative mechanism, integrin-growth factor receptor interactions, and explores the role of lipid rafts in the molecular mechanisms that underlie the receptor interactions. Copyright 2004 Biochemical Society

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 15157152 [PubMed - indexed for MEDLINE]

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10: Curr Pharm Des. 2003;9(19):1565-74.


Urokinase receptor and integrin interactions.

Kugler MC, Wei Y, Chapman HA.

Department of Medicine, Pulmonary and Critical Care Division, and CVRI University of California, San Francisco, 94143, USA.

Urokinase receptors (uPAR) were initially thought to function simply as a mechanism to concentrate the urokinase/plasmin system toward the cell surface. However, extensive evidence has accumulated that this glycolipid-anchored receptor also functions in both the adhesive and signaling pathways of many migratory cells. Mechanisms by which uPAR exercises these functions involve complexing with other membrane proteins for signal transduction. One set of functional partners for uPAR on the cell surface are integrins. Recent studies point to important structural features of uPAR:integrin interactions, indicating uPAR to be a cis-acting integrin ligand. In vivo data reveal altered integrin function and cell migration when uPAR:integrin interactions are impaired. Together these observations support the idea that uPAR:integrin interactions may be a focal point of intervention in pathobiology where integrin function is crucial, such as tumor metastasis.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 12871068 [PubMed - indexed for MEDLINE]

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11: Nephron. 2002;92(3):515-21.


Cellular interactions in the pathogenesis of human proliferative glomerulonephritis. The role of beta-2 integrin-expressing leukocytes.

Soma J, Sato H, Ootaka T, Saito T.

Second Department of Internal Medicine, Iwate Prefectural Central Hospital, Morioka, Japan. sjun@chuo-hp.pref.iwate.jp

Publication Types:
Review

PMID: 12372932 [PubMed - indexed for MEDLINE]

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12: Int J Hematol. 2001 Dec;74(4):382-9.


Platelet integrin alphaIIbbeta3-ligand interactions: what can we learn from the structure?

Kamata T, Takada Y.

Department of Anatomy, Keio University School of Medicine, Tokyo, Japan. kamata@sc.itc.keio.ac.jp

Upon vascular injury, platelets initiate interaction with exposed subendothelial matrices through various receptors such as glycoprotein (GP) Ib/IX/V complex, alpha2beta1 integrin, and GPVI/FcRgamma. Although these interactions cannot sustain stable platelet thrombus formation by themselves, they ultimately lead to the activation of alphaIIbbeta3 integrin (GPIIb-IIIa complex [GPIIb-IIIa]), the most abundant receptor in platelets. The alphaIIbbeta3 integrin plays a central role in primary hemostasis by serving as a receptor for fibrinogen and von Willebrand factor (vWf). It establishes a stable interaction with vWf bound to the extracellular matrices and uses fibrinogen as a bridging molecule in platelet aggregate formation. The alphaIIbbeta3 integrin also plays an important role in the pathogenesis of thrombosis. Over the past decades, a tremendous amount of effort has been made to elucidate the ligand-binding mechanisms of alphaIIbbeta3, in part because of its clinical significance. Most of the studies have relied on biochemical analyses of purified alphaIIbbeta3 or recombinant proteins generated in vitro. With the lack of actual 3-dimensional structure, molecular modeling has provided a useful framework for interpreting such experimental data on structure-function correlation of integrin molecules. However, it has also generated disagreement between different models. The aim of this minireview is to summarize the past efforts as well as the recent accomplishments in elucidating the structure/function of alphaIIbbeta3. Finally, we will try to explain all those experimental data using the recently published crystal structure of the extracellular domains of the alphaVbeta3 heterodimeric complex.

Publication Types:
Review

PMID: 11794692 [PubMed - indexed for MEDLINE]

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13: Osteoarthritis Cartilage. 2001;9 Suppl A:S131-40.


The molecular basis of integrin-extracellular matrix interactions.

Eble JA.

Institut für Physiologische Chemie und Pathobiochemie, Westfälische Wilhelms-Universität, Münster, Germany. eble@uni-muenster.de

Publication Types:
Review

PMID: 11680677 [PubMed - indexed for MEDLINE]

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14: Curr Opin Cell Biol. 2000 Oct;12(5):563-8.


T-lymphocyte-epithelial-cell interactions: integrin alpha(E)(CD103)beta(7), LEEP-CAM and chemokines.

Agace WW, Higgins JM, Sadasivan B, Brenner MB, Parker CM.

Immunology Section, Department of Cell and Molecular Biology, Lund University, Sweden.

The epithelia are the avascular layers of cells that cover the environment-exposed surfaces of the body. It appears that T cells localize to selected sites in or adjacent to epithelia via the selective expression of adhesion molecules and chemokine receptors on T cells. These bind to counter-receptors and to chemokines expressed by epithelial cells. Recently, there has been an advance in our understanding of the interaction of the alpha(Ebeta7) integrin with its epithelial cell ligand, E-cadherin. In addition, a new adhesion molecule has been identified on non-intestinal epithelial cells, termed lymphocyte-endothelial-epithelial-cell adhesion molecule (LEEP-CAM). Finally, there have been advances in our understanding of the role of skin- or gut-epithelia-derived chemokines in regulating activated T cell homing to these sites.

Publication Types:
Review

PMID: 10978890 [PubMed - indexed for MEDLINE]

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15: Bone. 1999 Jul;25(1):95-6.


Extracellular matrix-integrin interactions in osteoblast function and tissue remodeling.

Damsky CH.

Department of Stomatology, Schools of Dentistry and Medicine, University of California San Francisco 94143-0512, USA. damsky@cgl.ucsf.edu

Previous work with cultured primary cells, from our group and from other laboratories, has shown that signals from extracellular matrix, transduced by integrins, play critical roles in regulating gene expression, tissue-specific differentiation, and survival of primary osteoblasts and fibroblasts. This summary will focus on our most recent work, dealing with the role of cell-extracellular matrix interactions and focal adhesion kinase in regulating cell survival in osteoblasts and fibroblasts, and the role of beta1 integrins in tissue organization and remodeling in bone.

Publication Types:
Review

PMID: 10423030 [PubMed - indexed for MEDLINE]

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16: Front Biosci. 1997 Mar 1;2:d126-46.


Fibronectin-integrin interactions.

Johansson S, Svineng G, Wennerberg K, Armulik A, Lohikangas L.

Department of Medical and Physiological Chemistry, The Biomedical Center, Box 575, S-751 23 Uppsala, Sweden. staffan.johansson@bmc.uu.se

Fibronectin is recognized by at least ten cell surface receptors of the integrin family. Most cell types in the body can adhere to fibronectin via these receptors, and thereby fibronectin becomes involved in many different biological processes. Three areas related to fibronectin and its receptors which have developed rapidly during the last few years are summarized in this review: the mechanisms of interactions between fibronectin and integrins, fibronectin polymerization, and in vivo functions of the proteins as studied by gene targeting in mice.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 9159220 [PubMed - indexed for MEDLINE]

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17: Curr Opin Hematol. 1997 Jan;4(1):67-74.


Integrin-ligand interactions: scratching the surface.

Kanazashi SI, Sharma CP, Arnaout MA.

Department of Medicine, Massachusetts General Hospital, Charleston, USA.

Integrins provide cells with critical means of communication with their microenvironments. By linking events at the cell surface to a dynamic cytoskeleton-signaling complex, integrins enable cells to rapidly modify their mechanical and genetic machinery in response to environmental cues. This review highlights major advances made in understanding the structural basis of integrin-ligand interactions and their regulation.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 9050382 [PubMed - indexed for MEDLINE]

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18: Curr Opin Cell Biol. 1996 Oct;8(5):657-69.


Integrin cytoplasmic interactions and bidirectional transmembrane signalling.

Dedhar S, Hannigan GE.

Department of Medical Biophysics Division of Cancer Biology Research, Sunnybrook Health Science Centre, Reichmann Research Building, S-218, 2075 Bayview Avenue, Toronto, Ontario M4N 3M5, Canada.

Integrins are heterodimeric integral plasma membrane proteins containing extracellular, transmembrane, and cytoplasmic domains. These highly versatile receptors mediate not only cell adhesion and migration, but also the bidirectional transfer of information across the plasma membrane. The cytoplasmic domains of integrins are required for the transduction of this bidirectional information, and have recently been shown to participate in direct interactions with some novel cytoplasmic proteins, such as an ankyrin repeat containing serine/threonine protein kinase (integrin-linked kinase) and beta3 endonexin. New evidence also suggests that, via interactions with focal adhesion kinase, the integrin cytoplasmic domains can coordinate actin cytoskeletal organization and responses to growth factors. The elucidation of the signal transduction pathways activated by integrins is an intense area of investigation that has shown that integrins have some unique properties as signal transducing receptors.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 8939656 [PubMed - indexed for MEDLINE]

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19: Mol Neurobiol. 1996 Apr;12(2):95-116.


Role of laminin and integrin interactions in growth cone guidance.

McKerracher L, Chamoux M, Arregui CO.

Département de Pathologie, Université de Montréal, Quebec, Canada.

Laminin is well known to promote neuronal adhesion and axonal growth, but recent experiments suggest laminin has a wider role in guiding axons, both in development and regeneration. In vitro experiments demonstrate that laminin can alter the rate and direction of axonal growth, even when growth cone contact with laminin is transient. Investigations focused on a single neuronal type, such as retinal ganglion cells (RGCs), strongly implicate laminin as an important guidance molecule in development and suggest the involvement of integrins. Integrins are receptors for laminin, and neurons express multiple types of integrins that bind laminin. Morphologically, integrins cluster in point contacts, specialized regions of the growth cone that may coordinately regulate adhesion and motility. Recent evidence suggests that the structure and regulation of point contacts may differ from that of their nonneuronal counterpart, focal contacts. In part, this may be because the interaction of the cytoplasmic domain of integrin with the cytoskeleton is different in point contacts and focal contracts. Mutational studies where the cytoplasmic domain is truncated or altered are leading to a better understanding of the role of the alpha and beta subunit in regulating integrin clustering and binding to the cytoskeleton. In addition, whereas integrins may regulate motility through direct physical linkages to the growth cone cytoskeleton, an equally important role is their ability to elicit signaling, both through protein tyrosine phosphorylation and modulating calcium levels. Through such mechanisms integrins likely regulate the dynamic attachment and detachment of the growth cone as it moves on laminin substrates.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 8818145 [PubMed - indexed for MEDLINE]

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20: Chem Biol. 1995 Oct;2(10):639-43.


Ideas crystallized on immunoglobulin superfamily-integrin interactions.

de Fougerolles A, Springer TA.

Wellcome Trust Immunology Unit, University of Cambridge School of Clinical Medicine, UK.

Interactions between immunoglobulin superfamily (IgSF) members and integrins are central to lymphocyte homing, leukocyte emigration into tissues at inflammatory sites, and in cell-cell interactions that lead to immune responses. Recent X-ray crystal structures reveal that the interaction of a divalent cation found in the integrin structure with an acidic residue from the IgSF partner may be important in binding.

Publication Types:
Review

PMID: 9383469 [PubMed - indexed for MEDLINE]

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21: Curr Opin Cell Biol. 1994 Oct;6(5):656-62.


Integrin-ligand interactions: a year in review.

Haas TA, Plow EF.

Department of Molecular Cardiology, Cleveland Clinic Foundation, OH 44195.

Many cell-cell and cell-matrix interactions depend upon the engagement of specific ligands by members of the integrin family of cell-adhesion receptors. In concert with the identification of new integrins, the number of integrin ligands continues to expand dramatically. The diversity of the integrin ligands bridges many areas of cell and molecular biology. Ligand recognition by integrins requires not only the presence of the cognate primary sequence within an appropriate secondary structure, but also the correct tertiary and quaternary structure of the ligand. Presentation of an 'activated' ligand sequence to specific contact sites within the integrin under specified divalent-cation conditions is necessary for a productive and high-affinity interaction.

Publication Types:
Review

PMID: 7833046 [PubMed - indexed for MEDLINE]

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22: Adv Second Messenger Phosphoprotein Res. 1994;29:383-98.


Regulation of transmitter release by muscle length in frog motor nerve terminals. Dynamics of the effect and the role of integrin-ECM interactions.

Chen BM, Grinnell AD.

Department of Physiology, Jerry Lewis Neuromuscular Research Center, University of California, Los Angeles 90024.

Changes in muscle length cause large changes in the probability of transmitter release from frog motor nerve terminals. A 5% to 10% stretch from rest length can increase EPP amplitude or mEPP frequency by more than 100%. The phenomenon is fully reversible and extremely rapid. Within 7-10 milliseconds of the stretch, the enhancement is complete, and it is maintained essentially constant at the new level for as long as the stretch is sustained. Given these properties, the length modulation of release is unquestionably of functional importance, strongly amplifying the spinal stretch reflex. The stretch-induced enhancement of transmitter release persists at a reduced level in a 0 Ca++, 2 mM Mg++ Ringer. This finding indicates a lack of dependence on Ca++ influx from outside the terminal. Release of Ca++ from intracellular stores close to release sites cannot be ruled out as a contributing factor. Our results, however, suggest a mechanism involving physical connections between the extracellular matrix and the nerve terminal that can alter release probability directly. Morphological evidence for connections that might be responsible can be demonstrated in micrographs of deep-etched freeze fractures through neuromuscular junctions. Hypothesizing that the ECM-nerve terminal connections responsible for the stretch effect involve proteins from the integrin family and knowing that many of the integrin-ECM binding interactions occur at sites on the ECM proteins containing the amino acid sequence RGD, we treated preparations with 0 Ca++, 2 mM Mg++ Ringer to reduce integrin binding and then returned the muscle to normal Ringer containing 0.1-0.2 mM of a six-amino-acid peptide containing the RGD sequence. This peptide strongly suppressed the stretch effect, while a control peptide (RGE) had no effect. A 50 microM Ca++/50 microM Mg++ Ringer had little effect on stretch enhancement but permitted a strong inhibition of enhancement when RGD was present. The identity of the ECM molecule(s), the integrin(s), and the mechanism of enhancement of release are unknown. However, our findings imply that much or all of the length-dependent modulation of release probability is mediated by an RGD-sensitive integrin-ECM interaction that depends more on external Ca++ than on Mg++.

Publication Types:
Research Support, U.S. Gov't, P.H.S.
Review

PMID: 7848723 [PubMed - indexed for MEDLINE]

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23: Pathol Biol (Paris). 1992 Oct;40(8):813-21.


Disintegrins: RGD-containing proteins which inhibit cell/matrix interactions (adhesion) and cell/cell interactions (aggregation) via the integrin receptors.

Williams JA.

Protein Biochemistry, Thrombosis Research, Institute Emmanuel Kaye Building, Chelsea, London, England.

Whereas many attempts have been made to generate synthetic, high affinity, linear RGD-peptides (Arginine-Glycine-Aspartic acid), by analogy with glycoprotein ligands to integrins, success has been limited. What has emerged is that the stereochemistry of the Arg-Gly-Asp-X (RGDX) recognition sequence is essential to ligand binding. This has led to the study of small, chemically synthesised, cyclic-RGD peptides. Another approach is to study the disintegrins. These high-affinity RGD-polypeptides (50-90 KDa) from viper venoms are "natural" ligands to integrins, presumably as inhibitors of physiological ligands such as fibrinogen. A study of the disintegrins may shed some light on the preferred conformation of the active form of RGD, as well as the contribution of other potential recognition motifs in these molecules to modulate RGD interactions with receptors (fig. 1).

Publication Types:
Review

PMID: 1484742 [PubMed - indexed for MEDLINE]

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24: Chem Immunol. 1991;50:55-74.


Integrin alpha 4 beta 1: its structure, ligand-binding specificity and role in lymphocyte-endothelial cell interactions.

Ager A, Humphries MJ.

Department of Cell and Structural Biology, University of Manchester, UK.

Publication Types:
Review

PMID: 1786107 [PubMed - indexed for MEDLINE]

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25: J Cell Sci. 1990 Dec;97 ( Pt 4):585-92.


The molecular basis and specificity of integrin-ligand interactions.

Humphries MJ.

Department of Biochemistry and Molecular Biology, University of Manchester, UK.

Publication Types:
Research Support, Non-U.S. Gov't
Review

PMID: 2077034 [PubMed - indexed for MEDLINE]
 

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