Talk:2009 Lecture 13

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Lecture 12 and 13
School of Medical Sciences
The University of New South Wales Dr Mark Hill Cell Biology Laboratory Room G20 Wallace Wurth Building Email: m.h...)
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ANAT3231 - Cell Biology
Lecture 12 and 13
School of Medical Sciences
The University of New South Wales Dr Mark Hill Cell Biology Laboratory Room G20 Wallace Wurth Building Email: m.hill@unsw.edu.au

UNSW Copyright Notice ExtraCellular Matrix (ECM) Cell-Cell, Cell-Matrix Adhesions

ECM References Essential Cell Biology Ch19 p594-604 Molecular Biology of the Cell p971-1009 Animal and Plant ECM Material secreted and deposited by cells

ANAT3231 Lecture 8 Extracellular matrix http://cellbiology.med.unsw.edu.au/units/science/lecture0812.htm ECM Function

Support for cells
Pattern of ECM regulates

Polarity cell division adhesion motility Development migration differentiation Growth factors ECM Structure- Glycoproteins Fibers Collagen- main fibers Elastin Hydrated Matrix Proteoglycans high carbohydrate Adhesive Glycoprotein Laminin Fibronectin Shapes and Sizes ECM molecules Collagen tensile strength and elasticity Tendons Cartilage Bone half total body proteins (by weight) Collagen Components Insoluble glycoprotein protein + carbohydrate Protein high glycine and 2 modified amino acids hydroxylysine hydroxyproline (gly-X-Y)n Carbohydrate glucose galactose Collagen Structure Collagen Protein 3 polypeptide (a) chains left hand helix, forms fibers 14 different (vertebrate) collagens by different combinations of a-chains numbered I - XIV Type I, II, III main fibers, flexible Type I bone, skin, tendons 90% of all collagen Type II cartilage Collagen Fibers Type I, II, III cross striated showing overlapping packing of individual collagen molecules Type IV fine unstriated sheet-like supportive meshwork mature basal laminae tracks for embryonic migration barriers for cell migration Type V-XII smaller diameter fibers than I-III no striations Collagen Fibers Collagen Non-striated Collagen Synthesis Endoplasmic Reticulum mRNA attached to ER protein synthesized into ER lumen 3 proto-a-chains form soluble procollagen moved to golgi apparatus Golgi Apparatus packed into secretion vesicles fuse with membrane Outside Cell procollagen processed by enzymes outside cell assemble into collagen fibers Collagen Biosynthesis Collagen Diseases - Excess excess collagen fibrosis lung- pulmonary fibrosis overproduction of collagen I liver- over consumption of alcohol arteries- atherosclerosis Collagen Diseases - Insufficient insufficient collagen Ehlers-Danlos syndrome rubber-man skin and tendons easily stretched contortionists often suffer from this disease Osteogenesis imperfecta brittle-bone syndrome mutation in Type I procollagen fail to assemble triple helix degrade imperfect collagen Leads to fragile bones Collagen Diseases scurvy dietary Vitamin C deficiency needed for hydroxylation Proline -> Hydroxyproline form too few hydrogen bonds in collagen skin, bone, teeth weakness and malformation blood vessels weakened, bleeding Glycosaminoglycans (Gags) 10% by weight but fill most of space unbranched polysaccharide chains disaccharide subunits amino sugar 4 groups hyaluronan chondroitin sulphate, dermatan sulphate heparan sulphate, heparin keratan sulphate Glycosaminoglycans- Hyaluronan Also called hyluronic acid or hyaluronate Development produce a “cell-free” space for cell proliferation and migration into heart, cornea Adult in areas of compression tissues, joints Hyaluronan Synthesis synthesized at plasma membranes nascent chains directly extruded into ECM Proteoglycans Proteoglycans- Function trap water resistant to compression return to original shape occupy space link to collagen fibers form network in bone combined with calcium hydroxyapatite, calcium carbonate Cell adhesion embryonic migration Proteoglycan- Disease Cancer development altered types and kinds of proteoglycans formed by cells normal cells -> malignant Arthritis Cartilage breakdown chondrocytes elicit a catabolic response which exceeds anabolism of new matrix molecules Degrade proteoglycan (aggrecan) Also a mouse model generates antibodies to proteogycan Cell Adhesion to ECM Direct linkage to collagen or proteoglycan insertion of fibers into membrane covalent attachment to membrane lipid Linking glycoproteins fibronectin laminin Fibronectin Structure Fibronectin Structure dimer connected at C-terminal S-S linkages rigid and flexible domains cell binding segment RGDS arg-gly-asp-ser binds receptor in membrane domains bind heparin sulphate Collagen hyaluronic acid Gangliosides fibronectin Fibronectin Function cell adhesion migration pathways blocking fibronectin with antibody

prevents neural crest migration
extension of axons and dendrites

branching Differentiation basal laminae under skin and between organs blood clotting process, link to fibrin Laminin Laminin Structure Laminin Structure cross-shaped glycoprotein 3 polypeptides a, b1, b2 carbohydrate (13% by weight) Mr 900K separate binding domains collagen IV heparin heparin sulphate cell binding cell specific binding liver, nerve

cell surface receptor

Laminin Function cell adhesion migration pathways stimulates growth of axons development and regeneration differentiation basal laminae most abundant linking glycoprotein Integrin- Structure Integrin Function cell membrane receptor for ECM linkers binds RGDS motif 2 subunits alpha (α) and beta (β) transmembrane linked to cell cytoskeleton actin microfilaments via talin and vinculin focal contacts For Review see Integrin signaling revisited. Schwartz MA.Trends Cell Biol 2001 Dec;11(12):466-70 Focal Adhesions- Microfilaments Cell signalling Modify cell cytoskeleton Activate intracellular signalling pathways Cell motility Integrin- Function Activate members of Rho-family of small GTPases Conversely, Rho- and Ras-family proteins can influence the ability of integrins to bind their ligands control of cell motility, and therefore on invasive and metastatic behavior Integrin binding ECM has effects on cell survival, particularly for cells of epithelial origin specific integrins have selective effects on efficiency of signal transduction in cell survival pathways Text modified from: New aspects of integrin signaling in cancer. Semin Cancer Biol 2000 Dec;10(6):407-14 Integrin Signaling Adhesive Signalling Integrin and Laminin Several integrin heterodimers act as laminin receptors on a variety of cell types alpha 1 beta 1 alpha 2 beta 1 alpha 3 beta 1 alpha 6 beta 1 alpha 7 beta 1 alpha 6 beta 4 Microsc Res Tech 2000 Nov 1;51(3):280-301 Integrin and Laminin Roles of laminin-binding integrins in adhesion-mediated events in vertebrates embryonic development, cell migration and tumor cell invasiveness, cell proliferation, differentiation and basement membrane assembly essential role for receptors in maintaining cell polarity and tissue architecture Text from: Microsc Res Tech 2000 Nov 1;51(3):280-301 Basal Lamina Experiment 1 Basal Lamina Experiment 2 Neuromuscular junction Basal lamina directs acetylcholinesterase (AChE) accumulation at synaptic sites in regenerating muscle skeletal muscle damaged such that basal lamina sheaths of the muscle fibers spared new myofibers develop within sheaths and neuromuscular junctions form at original synaptic sites regenerated neuromuscular junctions have junctional folds and accumulations of acetylcholine receptors and AChE Anglister L, McMahan UJJ Cell Biol 1985 Sep;101(3):735-43 Adhesion Junctions Adherens (cell-cell) cadherin (E-cadherin) Links to cadherin in neighboring cell Adherens (cell-matrix) Integrin Links to extracellular matrix ECM Scaffold- Tissue Engineering “Decellularized tissues and organs have been successfully used in a variety of tissue engineering/regenerative medicine applications, …Each of these treatments affect the biochemical composition, tissue ultrastructure, and mechanical behavior of the remaining extracellular matrix (ECM) scaffold, which in turn, affect the host response to the material.” Decellularization of tissues and organs. Biomaterials. 2006 Jul;27(19):3675-83. Epub 2006 Mar 7.