ch3_integrin

ch3_integrin - Harvard-MIT Division of Health Sciences and...

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Unformatted text preview: Harvard-MIT Division of Health Sciences and Technology HST.523J: Cell-Matrix Mechanics Prof. Myron Spector Massachusetts Institute of Technology Massachusetts Harvard Medical School Brigham and Women’s Hospital VA Boston Healthcare System 2.785j/3.97J/BEH.411/HST523J INTEGRINS M. Spector, Ph.D. and I.V. Yannas, Ph.D. UNIT CELL PROCESSES UNIT Regulator UCP Cell + Matrix Connect. ECM Tiss. Adhesion Epithelia Protein Muscle Collagen Nerve Biomaterial Integrin Product + Regulator Mitosis Synthesis Migration Contraction Endocytosis Exocytosis The Cell and Its Membrane Molecules The Cell and Its Membrane Molecules Figures by MIT OCW. After Darnell et al., Molecular Cell Biology, 1990. CELL ADHESION MOLECULES CELL Type Integrin * Homophilic • N-CAM • Cadherin Heterophilic Cell-Matrix √ Cell-Cell √ √ √ * Integrins bind to adhesion proteins and some to collagen Integrins Schematic of a typical integrin The RGD* amino acid sequence on adhesion proteins (e.g., fibronectin) was identified as the integrin-binding region (i.e., the ligand for integrin receptors) – E Ruoslathi and MD Pierschbacher, Sci., 238:491 (1987) * arginine-glycine-aspartic acid Figure by MIT OCW. After Albelda and Buck, FASEB J., 4:2868 (1990) Integrin Signaling, FG Giancotti, E Ruoslahti, Sci., 285:1028 (1999) Diagram removed for copyright reasons. Figure 2. Matrix binding promotes integrin clustering and association with the cytoskeleton. This in turn promotes further integrin clustering and matrix organization in a positive feedback system. Cytoskeletal Component Proposed Model of Fibroblast Focal Adhesion In Vitro In Vitro Courtesy of The Journal of NIH Research. Used with permission. Courtesy of the Journal of the NIH. J NIH 5:50 (1993) J NIH 5:50 (1993) Rat Fibroblast on Culture Dish Fluorescent stains for actin (green) and focal adhesion kinase (red) Border of the cell on the culture dish Courtesy of the Journal of NIH. J NIH 5:49 (1993) INTEGRINS AND THEIR LIGANDS α2 α3 β4 α6 α7 α8 α1 α10 β3 β5 αII β1 α5 αν β6 Collagen Laminin Fibronectin Fibrinogen Vitronectin α4 β7 Adapted from: http://www.scripps.edu/cb/gardner/integrins.htm (from http://life.kjist.ac.kr/htm/lab/cell/integrin/integrin.htm) Integrins are membrane-bound molecules (receptors) that can bind to are membrane that extracellular matrix molecules (“adhesion proteins” and collagen). They are extracellular ). the principal mechanism by which cells both bind to and respond to the the to extracellular matrix. They are part of a large family of cell adhesion extracellular hesion molecules which are involved in cell-extracellular matrix and cell-cell molecules cell interactions. Functional integrins consist of two transmembrane glycoprotein integrins consist transmembrane glycoprotein subunits that are non-covalently bound. Those subunits are called alpha and subunits covalently beta. The alpha subunits all have some homology to each other, as do the beta beta. do subunits. The receptors always contain one alpha chain and one beta chain and are thus called heterodimeric. Both of the subunits contribute to the heterodimeric Both binding of ligand. Until now 16 alpha and 8 beta subunits have been binding een identified. From these subunits some 22 integrins are formed in nature, which integrins are implicates that not all possible combinations exist. The beta-4 subunit for imp subunit instance can only form a heterodimer with the alpha-6 subunit. On the other heterodimer subunit. hand the beta-1 subunit can form heterodimers with ten different alpha subunit heterodimers with hand subunits. Because not all the beta-1 alpha heterodimers have the same ligand subunits. alp heterodimers have specificities, it is believed that the alpha chain is at least partly involved in the specificities, artly ligand specificity. INTEGRINS INTEGRINS (from http://life.kjist.ac.kr/htm/lab/cell/integrin/integrin.htm) Integrins differ from other cell-surface receptors in that they bind their surface ligands with a low affinity (106-109 liters/mole) and that they are usually ligands 109 present at 10-100 fold higher concentration on the cell surface. The present 100 integrins however can only bind their ligands when they exceed a certain integrins ho minimal number of integrins at certain places, called focal contacts and integrins at hemidesmosomes. So when the integrins are diffusely distributed over hemidesmosomes So integrins are the cell surface, no adhesion will be present, but when after a certain stimuli these integrins cluster for example in focal contacts their integrins cluster combined weak affinities give rise to a spot on the cell surface which has combined which enough adhesive (sticking) capacity to adhere to the extracellular enough ar matrix. This is a very useful situation, because in this way cells can bind matrix. ls simultaneously but weakly to large numbers of matrix molecules and simultaneously nd still have the opportunity to explore their environment without losing all attachment to it by building or breaking down focal contacts. If the attachment the receptors were to bind strongly to their ligands, cells would probably be receptors obably irreversibly bound to the matrix, depriving them from motility. This problem does not arise when attachment depends on multiple weak adhesions. INTEGRINS INTEGRINS (from http://life.kjist.ac.kr/htm/lab/cell/integrin/integrin.htm) Integrins can bind to an array of ligands. Common ligands are can fibronectin and laminin, which are both part of the CT laminin which extracellular matrix and basal lamina. Both of these ligands mentioned above are recognized by multiple integrins. For integrins For adhesion to ligands both integrin subunits are needed, as is the integrin subunits presence of cations. The alpha chain has cation binding sites. cations The cation binding Integrins are composed of long extracellular domains which Integrins are adhere to their ligands, and short cytoplasmic domains that cytoplasmic domains link the receptors to the cytoskeleton of the cell. The structure of alpha subunits is very similar. All contain 7 homologous repeats of 30-40 amino acids in their extracellular homologous 40 domain, spaced by stretches of 20-30 amino acids. The three or domain, 30 four repeats that are most extracellular, contain sequences with cation-binding properties. These sequences are thought to cation binding be involved in the binding of ligands, because the interaction of be integrins with their ligand is cation-dependent. integrins with cation dependent. INTEGRINS INTEGRINS Integrin Signaling Diagram removed for copyright reasons. See Figure 1 in Giancotti, FG and E Ruoslahti, Science 285:1028 (1999) Cell survival and cell proliferation require interaction with the extracellular matrix. Epithelial cells in some tissues, such as skin and gut, are continuously renewed from stem cells that rest on a basement membrane. Neighboring cells migrate into the space left empty by cells that have moved away to differentiate. Certain epithelia, such as those of the mammary gland and prostate, are not continuously renewed. In this case, interaction with the matrix appears to promote differentiation. During involution, the basement membrane is dissolved by proteolysis, and the cells undergo apoptosis. Integrin Signaling Diagram removed for copyright reasons. See Figure 4 in Giancotti, FG and E Ruoslahti, Science 285:1028 (1999) This diagram shows signaling pathways that are known or presumed to be coordinately regulated by integrins and growth factors receptors. These pathways control immediate-early gene expression, the cell cycle machinery, and cell survival. Diagram removed for copyright reasons. Figure 2, “Schematic representation of the modulation of microvascular endothelial cell phenotype during angiogenesis.” In Madri, Kidney Int. 41:562 (1992) ...
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This note was uploaded on 11/11/2011 for the course BIO 20.410j taught by Professor Rogerd.kamm during the Spring '03 term at MIT.

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