麻省理工大学：《生物材料——组织交互作用》教学讲义（英文版）UNIT CELL PROCESSES

Massachusetts Institute of Technology yE图 Harvard medical school Brigham and women's hospital VA Boston Healthcare System 2.79J/3.96J/BE.441/HST522J INTEGRINS I.V.Yannas, Ph. D, and M. spector, Ph.D

Massachusetts In Massachusetts Institute of Technology stitute of Technology Harvard Medical School Harvard Medical School Brigham and Wo Brigham and Women’s Hospital men’s Hospital VA Boston Healthcare System VA Boston Healthcare System 2.79J/3.96J/BE.441/HST522J 2.79J/3.96J/BE.441/HST522J INTEGRINS INTEGRINS I.V. Yannas, Ph.D. and M. Spector, Ph.D. I.V. Yannas, Ph.D. and M. Spector, Ph.D

UNIT CELL PROCESSES Regulator UCP Cell Matrix Product Regulator Connect ECM Mitosis Tiss Adhesion ynthesis Epithelia Protein Migration Muscle Collagen Contraction Nerve Biomaterial Endocytosis Integrin Exocytosis

UNIT CELL PROCESSES UNIT CELL PROCESSES Cell + Matrix Product + Regulator Cell + Matrix Product + Regulator Regulator Regulator Mitosis Mitosis Synthesis Synthesis Migration Migration Contraction Contraction Endocytosis Endocytosis Exocytosis Exocytosis UCP Connect. Connect. Tiss. Epithelia Epithelia Muscle Nerve ECM Adhesion Adhesion Protein Protein Collagen Collagen Biomaterial Biomaterial Integrin Integrin

The cell and its membrane molecules Plasma membrane -5nm Rough ER Smooth Er Nucleus -3-10 um Nucleolus Nuclear pore Golgi complex Extracellular Cilia Oligosaccharide Glycoprotein Peripheral Glycolipid Integral 1 um Mitochondrian hydrophobic cytoskeletal fibers Hydrophilic Intracellular

The Cell and Its Membrane Molecules

CELL ADHESION MOLECULES Type Cell-Matrix ell-Cell Integrin Homophilic N-CAM Cadherin Heterophilic Integrins bind to adhesion proteins and some to collagen

CELL ADHESION MOLECULES CELL ADHESION MOLECULES Type Cell -Matrix Cell -Cell Integrin Integrin * √ √ Homophilic Homophilic • N -CAM • Cadherin Cadherin √ Heterophilic Heterophilic √ * Integrins Integrins bind to adhesion proteins and some to collagen bind to adhesion proteins and some to collagen

Ligand binding After sM albelda. cA Buck eglon FASEB J.,4:2868(1990) β subunit Ca* a subunit Schematic of a typical integrin s S-S I Xe Extracellular The RGD*amino acid sequence on domain Membrane adhesion proteins(e.g, fibronectin)was identified as the integrin-binding region (i.e, the ligand for integrin receptors) Tatin E Ruoslathi and md pierschbacher Vinculin Sci,238:491(1987) a-actinin arginine-glycine-aspartic acid Actin cytoskeleton

After SM Albelda, CA Buck, FASEB J., 4:2868 (1990) 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

Integrin Signaling, FG Giancotti,E Ruoslahti, Sci, 285: 1028(1999) Image removed due to copyright considerations 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 feed back system. RGD, Arg-Gly-Asp integrin-binding motif; Tal, talin; Pax, paxillin; Vin, vinculin; CAS, p130CAS

Integrin Signaling, FG Giancotti, E Ruoslahti, Sci., 285:1028 (1999) Image removed due to copyright considerations. 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. RGD, Arg-Gly-Asp integrin-binding motif; Tal, talin; Pax, paxillin; Vin, vinculin; CAS, p130CAS

Image removed due to copyright considerations

Cytoskeletal Component Proposed Model of Fibroblast Focal Adhesion In Vitro Image removed due to copyright considerations. J NIH 5:50 (1993)

Image removed due to copyright considerations

Rat Fibroblast on Culture Dish Fluorescent stains for actin (green) and focal adhesion kinase (red) Border of the cell on the culture dish Image removed due to copyright considerations. J NIH 5:49 (1993)

INTEGRINS AND THEIR LIGANDS a2 β3 a 3 010 β4 阝5 6-β1 阝6 8 5 Collagen 4 amini ■■ Fibronectin Fibrinogen Vitronectin Adaptedfromhttp://www.scripps.edu/cb/gardner/integrins.htm

INTEGRINS AND THEIR LIGANDS β 1 αν α 5 α 4 α 8 α 7 α 6 α 3 α 2 α 1 α10 β 3 β 5 β 6 αII β 4 β 7 Collagen Laminin Fibronectin Fibrinogen Vitronectin Adapted from: http://www.scripps.edu/cb/gardner/integrins.htm

INTEGRINS (fromhttp://ife.kjist.ac.kr/htm/ab/cell/integrin/integrin.htm) Integrins are membrane-bound molecules(receptors) that can bind to extracellular matrix molecules( adhesion proteins"and collagen). They are the principal mechanism by which cells both bind to and respond to the extracellular matrix. They are part of a large family of cell adhesion molecules which are involved in cell-extracellular matrix and cell-cell interactions. Functional integrins consist of two transmembrane glycoprotein subunits that are non-covalently bound. Those subunits are called alpha and beta. The alpha subunits all have some homology to each other, as do the beta subunits. The receptors always contain one alpha chain and one beta chain and are thus called heterodimeric. both of the subunits contribute to the binding of ligand. Until now 16 alpha and 8 beta subunits have been identified From these subunits some 22 integrins are formed in nature, which implicates that not all possible combinations exist. The beta-4 subunit for instance can only form a heterodimer with the alpha-6 subunit On the other hand the beta-l subunit can form heterodimers with ten different alpha subunits Because not all the beta-1 alpha heterodimers have the same ligand specificities, it is believed that the alpha chain is at least partly involved in the ligand specificity

INTEGRINS INTEGRINS (from http://life. (from http://life.kjist.ac.kr /htm/lab/cell/ /lab/cell/integrin integrin/integrin integrin.htm ) Integri Integri n s are membrane membrane -bound molecules (receptors) bound molecules (receptors) that can bind to that can bind to extracellular matrix molecules (“ extracellular matrix molecules (“adhesion proteins” and collagen adhesion proteins” and collagen). They are ). They are the principal mechanism by whic the principal mechanism by which cells both bind to and respon h cells both bind to and respond to the d to the extracellular extracellular matrix. They are part matrix. They are part of a large fam of a large fam ily of cell ad ly of cell adhesion molecules which are involved in cell molecules which are involved in cell-extracellular matrix and cell extracellular matrix and cell-cell interaction interaction s. Functional . Functional integrin integrin s consist of two consist of two transmembrane transmembrane glycoprotein glycoprotein subunits that are non subunits that are non -covalently bound. Those subunits are called alpha and covalently bound. Those subunits are called alpha and beta. The alpha subunits all have some homology to each other, a beta. The alpha subunits all have some homology to each other, as do the beta s do the beta subunits. subunits. The receptors always contain one The receptors always contain one alpha chain and one beta chain alpha chain and one beta chain and are thus called and are thus called heterodimeric heterodimeric. Both of the subunits contribute to the . Both of the subunits contribute to the binding of ligand. Until now 16 alpha and 8 beta subunits have b binding of ligand. Until now 16 alpha and 8 beta subunits have been identified. From these subunits some 22 identified. From these subunits some 22 integrins integrins are formed in nature, which are formed in nature, which implicates th licates that not all possib at not all possib le combinations exist. The beta e combinations exist. The beta -4 subunit for 4 subunit for instance can only form a stance can only form a heterodimer heterodimer with the alpha with the alpha -6 subunit. On the other 6 subunit. On the other hand the beta hand the beta -1 subunit can form 1 subunit can form heterodimers heterodimers with ten different alpha with ten different alpha subunits. Because not all the beta subunits. Because not all the beta -1 alp ha heterodim heterodimers have the same ligand have the same ligand specificities, it is believed that specificities, it is believed that the alpha chain is at least p the alpha chain is at least partly involved in artly involved in the ligand specificity. ligand specificity