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MULTICELLULAR ORGANISMS Cell-Cell Adhesion Cell-Matrix Adhesion The Extracellular Matrix, ECM M. Habibi-Rezaei.

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Presentation on theme: "MULTICELLULAR ORGANISMS Cell-Cell Adhesion Cell-Matrix Adhesion The Extracellular Matrix, ECM M. Habibi-Rezaei."— Presentation transcript:

1 MULTICELLULAR ORGANISMS Cell-Cell Adhesion Cell-Matrix Adhesion The Extracellular Matrix, ECM M. Habibi-Rezaei


3 Cell-Cell Interactions

4 Cleavage

5 MULTICELLULAR ORGANISMS The appearance of multicellular organisms allows specialization of cells and formation of organs Vertebrates have more than 100 specialized cell types (plants have more than 15) A special matrix, the extracellular matrix, ECM, fills out the space between cells

6 Cell Signals Direct contact Paracrine signaling Endocrine signaling –hormones Synaptic signaling –neurotransmitters

7 Cell Signaling

8 Cell Surface Receptors

9 MULTICELLULAR ORGANISMS By means of cell adhesion molecules, CAMs, cells are capable of recognizing each other Plasma membrane receptors take care of cell-ECM interactions



12 CELL-CELL ADHESION MOLECULES Cadherins Ig superfamily CAMs Selectins Integrins

13 Functional Categories of Cell Junctions Occluding Tight Junctions AnchoringCommunication Adherens Junctions Desomosomes Focal Adhesions Hemi- desmosomes Gap Junctions Chemical Synapses Plasmodesmata (Plants) Cadherin Integrin Septate Junctions (Invertebrates)

14 Adhesion Molecules and Extra Junctional Adhesion: Types of cell-cell adhesion

15 Cell adhesion Emphasis on cell migration: –Embryogenesis –Immune cell chemotaxis –Tumor cell metastasis Types of adhesion molecules involved in these processes

16 Major Families of Cell Adhesion Molecules (CAMs) Cadherins: participate in adherens junctions (adhesion belts) & desmosomes Immunoglobulin-like CAMs (ICAMs): only extrajunctional Integrins: cell matrix adhesion, hemidesmosomes, focal contacts Selectins: transient adhesion of leucocytes to blood vessels Integral membrane proteoglycans

17 Cell-Cell Recognition and Adhesion What are the different categories of adhesion receptors? What is the difference between homophilic and heterophilic interactions?



20 CADHERINS A family of Ca 2+ -dependent CAMs Ca 2+ causes dimerization of Cadherins The binding is homophilic

21 Cadherins – Ca ++ dependent Homophilic binding

22 Cadherins are Responsible for Cell-Cell Adhesion

23 Cadherins are homophilic, calcium dependent adhesion molecules

24 Primary tumor suppressor function of E- cadherin Sequesteration of cytoplasmatic pools of ß-catenin Which prevents ß-catenin Of entering the nucleus and starting transcription programm

25 Cadherins Mediate Cell Sorting Due to Homophilic Binding 1) The type of cadherins they express 2) The level of cadherins they express Cells in culture sort themselves based upon:

26 Adherens Junctions Help Fold Epithelial Cells Fig

27 Embryogenesis & Cadherins Expression of specific cadherins accompanies morphogenetic movements during embryogenesis



30 Integrins - Binding to extracellular matrix Protease cleaves Talin; binding/ uncoupling with actin Tripeptide binding sequence


32 Immunoglobulin Superfamily CAMs (ICAMs) Important during neural development Binding is calcium-independent


34 SELECTINS Selectins are involved in extravasation Inflammatory signals activate endothelial cells making P-Selectin undergo exocytosis P-Selectin on the surface of endothelial cells binds a specific carbohydrate ligand (Sialyl Lewis -x) on leukocytes The leukocytes attach to the endothelial wall and roll slowly on it PAF and integrins are then activated and the leukocytes start to extravasate

35 Selectins mediate adhesions of white blood cells (leukocytes) during extravasation (migration of cells out of blood vessels) Adhesion is weak & transient Involved in other process, including adhesion of early embryo to uterine wall

36 Model of Extravasation


38 Integrins are Heterodimers

39 dimerized single-transmembrane proteins consist of alpha and beta subunits, (18 a-subunit members and 8 b-subunit members) combine to form at least 25 different integrin receptors fibronectin, vitronectin, laminin, collagen etc. focal adhesion complex. ECM molecules

40 INTEGRINS serve as a velcro for cell migration In resting cell, most of the integrins are inactive (Not ligand-binded) In moving cell, integrins are turned on in front of cell, griping to ECM and pulling. At back, integrins are off. Internalised and recycled The cell moves by actin-driven "ruffling" it's membrane.

41 Focal Adhesions: Connect Cells to the EC Matrix Integrins Attach actin filaments from cell to matrix Connect to cytoplasmic anchor proteins Adhesion Proteins Anchor Proteins Fig

42 Circ Res 89:

43 Integrins and their ligands J Biol Chem 275:21785, 2000

44 Integrin Clustering Mediates Intracellular Signaling


46 Extracellular Matrix Forms diverse structures Bone Ligament Tendon Vessel Connective tissue Skin Biological processes Adhesion Mechanical support Migration Proliferation Signalling Diseases Arthritis Atherosclerosis Cancer Asthma

47 Extracellular Matrix Prominent in Connective Tissues

48 Figure 4.1

49 Extracellular Matrix is Contains of 3 Main Components: Proteoglycans Collagens Multi Adhesive Matrix Proteins Perlecan Large ( aggrecan, versican) Small ( decorin, Biglycan, Fibromodulin, Lumicin) At least 12 types Fibronectin Laminin Nidogen Entactin

50 ECM Basement Membrane thin extracellular layer made up of –basal lamina closest to epithelial cells secreted by epithelial cells Components –reticular lamina deep to basal lamina part of connective tissue layer produced by fibroblasts

51 Composition of The Extracellular Matrix BoneCornea

52 MAJOR ECM CONSTITUENTS Hyaluronan Proteoglycans Collagens Elastin Fibronectin Laminin Enactin/nidogen Protein in green, glycosaminoglycan in red.


54 Glycosaminoglycan ( GAG) Chains are Composed of a Repeating Disaccharide Sequence Contains carboxyl & sulfate groups (-) Charge

55 Hyaluronan is a GAG Chain Composed of a Repeating Disaccharide Sequence Does not form proteoglycans; Contains only carboxyl groups (-) Charge 19-38

56 HYALURONAN Relative volumes

57 Some Common Proteoglycans

58 Proteoglycans = GAG Chain + Core Protein 19-39

59 Proteoglycans & Hyaluronan Associate to Form Large Complexes in the ECM 19-41


61 Basal Lamina Some functions: –Provide structural definition & integrity to tissues –Acts as selective filter of small compounds –Determines cell polarity –Organize cell surface proteins on adjacent cell membranes –Promotes cell survival, proliferation, differentiation –Serves as pathway for cell migration

62 Basil Lamina: a specialized sheet of ECM

63 21_019.jpg Scanning Electron Micrograph of an Epithelium

64 Composition of Basal lamina


66 Collagen

67 COLLAGENS A helix comprised of homotrimer & heterotrimer polypeptides (alpha chains) Major proteins of ECMs Many different alpha chains Multiple structures (involves cross-linking of chains) fibrils fibril-associated network forming Fig

68 Some types of collagen & their properties

69 Formation of Collagen FIBRILS and FIBERS

70 Formation of Collagen Networks

71 COLLAGEN ASSEMBLIES Ann Med 33:7, 2001


73 LAMININ Heterotrimeric glycoprotein Basal lamina constituent Multiple binding domains

74 74 2. Laminin i. a cross-shaped-protein with four binding sites for: i. cells trans-membrane proteins including integrins ii. other laminins, iii. proteoglycans and iv. collagen. : thus forming networks of extracellular fibers, including an inter- laced web in the basement membrane 3. entactin. another web-forming protein found in the basement membrane. Lin

75 Binding Domains of Laminin Self assembly Type IV collagen Heparan sulfate Enactin/nidogen Cell Surface –integrin –nonintegrin J. Anat. 193:1, 98 Cell Suface Binding Sites


77 FIBRONECTIN (FN) Extracellular dimeric glycoprotein Differential splicing Multiple functional domains –cell binding RGD sequence of FN other specificities –heparin binding –collagen binding –fibrin binding Organized into a matrix Fig A,C

78 78 5. fibronectin. Important multi-valent linker. Multiple recognition sites on each of two peptides. constructed of two similar (not identical) peptides joined by disulfide bridges. A family of proteins. –Each one has modular construction, with multiple binding sites for components of the ECM: i. collagen, ii. proteoglycans, –integrins an arg-gly-asp amino acid (RGD) sequence –functions to make a web of proteins, proteoglycans and cells by cross linking them –Especially important as binding sites for cells within the ECM due to integrin binding. H2NH2N ss ss COOH H2NH2N Collagen proteoglycan laminin integrin


80 Matrix Metalloproteases MMPs

81 Genes Dev 14:2123,00

82 Matrix Metalloproteases

83 Distintegrin and Metalloproteinase (ADAM) ADAM proteins are members of the same superfamily as MMPs, namely the Metzincins, named for their zinc binding domains and their structurally important C- terminal conserved methionine residue. The name ADAM stands for A Disintegrin And Metalloprotease and like the name suggests, ADAM proteins are cell surface proteins that possess both an adhesion domain as well as a protease domain (Wolfsberg, TG et al. J Cell Biol 1995; 131:275–278). There are more than 35 members of the ADAM family of proteins; the precise function of many the ADAM family members are unknown, but some, such as ADAM17 (a.k.a. tumor necrosis factor–a converting enzyme) have known biological functions. An additional class of ADAM related proteins are known as the ADAMTS proteins. ADAMTS proteins are structurally homologous to ADAM proteins, but they contain at least one C-terminal thrombospondin type 1 (TSP1) repeat and are secreted rather than membrane bound. ADAMTS1 and ADAMTS8 are inhibitors of angiogenesis, and others, such as ADAMTS5, cleave extracellular proteoglycans such as aggrecan. ADAM A Disintegrin And Metalloprotease

84 Trends Genet. 16:83, 00 A disintegrin is a molecule that binds to an integrin. T = transmembrane domain

85 Trends Genet. 16:83, 00


87 Tumor Cell Metastasis

88 Proteases allow cells to move through ECM, basal lamina White blood cells Tumor cells

89 CELL JUNCTIONS Adherens junctions Gap junctions Tight junctions Desmosomes/Hemidesmosomes Focal adhesions

90 Cell-Matrix Interactions







97 Lectin familyTypical saccharide ligandsSubcellular locationExamples of functions CalnexinGlc 1 Man 9 ER Protein sorting in the endoplasmic reticulum. M-type lectinsMan 8 ER ER-associated degradation of glycoproteins. L-type lectinsVariousER, ERGIC, Golgi Protein sorting in the endoplasmic reticulum. P-type lectinsMan 6-phosphate, othersSecretory pathway Protein sorting post-Golgi, glycoprotein trafficking, ER-associated degradation of glycoproteins, enzyme targeting. C-type lectinsVarious Cell membrane, extracellular Cell adhesion (selectins), glycoprotein clearance, innate immunity (collectins). Galectins -Galactosides Cytoplasm, extracellular Glycan crosslinking in the extracellular matrix. I-type lectins (siglecs)Sialic acidCell membraneCell adhesion. R-type lectinsVariousGolgi, Cell membrane Enzyme targeting, glycoprotein hormone turnover. F-box lectinsGlcNAc 2 CytoplasmDegradation of misfolded glycoproteins. FicolinsGlcNAc, GalNAc Cell membrane, extracellular Innate immunity. Chitinase-like lectinsChito-oligosaccharidesExtracellularCollagen metabolism (YKL-40). F-type lectinsFuc-terminating oligosaccharidesExtracellularInnate immunity. IntelectinsGal, galactofuranose, pentoses Extracellular/cell membrane Innate immunity. Fertilization and embryogenesis. Summary of lectin families

98 Common nameGeneIsoforms [a]a LOF phenotype(s) [b]b References Collagen IV α1emb-91Emb (2-3X) Guo et al., 1991Guo et al., 1991; Gupta et al, 1997Gupta et al, 1997 Collagen IV α2let-22Emb (2-3X)Sibley et al., 1993Sibley et al., 1993, Collagen XVIIIcle-14Neuro, gonad morph Ackley et al., 2001Ackley et al., 2001, Fibulin-1fbl-12Gonad morph Hesselson et al., 2004Hesselson et al., 2004; Kubota et al., 2004 Kubota et al., 2004 Hemicentinhim-42 Tissue adhesion, aneuploidy Vogel and Hedgecock, 2001 Laminin αAlam-31Emb, AccHuang et al., 2003 Laminin αBepi-12Emb, Acc, SteHuang et al., 2003 Laminin βlam-11N.D. Laminin γlam-21N.D. Nidogennid-13Neuro Kang and Kramer, 2000Kang and Kramer, 2000; Kim and Wadsworth, 2000Kim and Wadsworth, 2000 Osteonectin/SPARCost-11Acc (L1-L2) Fitzgerald and Schwarzbauer, 1998 Papilinppn-13Emb (hyp enclosure)hypKramerova et al., 2000 Perlecanunc-52>5Pat Rogalski et al., 1993Rogalski et al., 1993,


100 COLLAGENS The most abundant animal protein At least 16 types exist The structural unit is composed of three 300 nm long coiled subunits in a triple helix The helical structure depends on the abundant presence of glycin, proline (and hydroxyproline) making a motif gly-pro-x, which is necessary for twisting together the three strands


102 COLLAGENS 2 Collagens are synthesized as precursors called procollagens They are glycosylated in ER and Golgi adding Gal and Gly to hydroxy-lysine residues and long oligosaccharides to selected asparagine residues Proline and lysine are hydroxylated Disulphide bonds are made between the N- and C- terminal parts of the propeptides After exocytosis the N- and C-terminals are trimmed, only then can the fibrils be formed

103 COLLAGENS 3 Lack of vitamin C prevents hydroxylation impaired fibrils Mutations or deletions of -chains in Collagen I can lead to the disease Osteogenesis imperfecta



106 LAMININ Laminin is a key component of the basal lamina







113 DISEASES OF THE BASAL LAMINA Alports syndrome appears as impaired ultrafiltration in the kidney resulting in renal failure and hearing loss. Mutations in collagen IV -chains result in this syndrome. Antibodies against 3-chains of collagen IV lead to pulmonary hemorrhage and renal failure (Goodpastures syndrome)

114 FIBRONECTIN Fibronectins attach cells to collagens Fibronectins are dimers Fibronectins express the RGD sequence recognized by integrins


116 PROTEOGLYCANS 1 The Polysaccharides in proteoglycans are long repeating polymers of dissacharides called Glucosaminoglycans (GAGs) One sugar of the dissacharides is a uronic acid and the other is an aminosugar (e.g. N- acetylglucosamine) One or both sugars contain one or two sulphate residues




120 HYALURONAN (HA) HA is a GAG found in ECM HA is also a key component of complex proteoglycans HA consists of approx. 50,000 disaccharides in a random coil. It can be bound to the surface receptor CD44 HA gives strength, flexibility and smoothness to the ECM and forms a viscous hydrated gel in which cells can migrate HA makes the ECM able to resist compression

121 PROTEOGLYCANS 2 Heparin sulphate and chondroitin sulphate are added to a 3-sugar linker (Xyl-Gal- Gal) added to a Serine in the core protein Proteoglycans are found both in ECM and attached to the plasma membrane



124 PROTEOGLYCANS IN THE ECM In cartilage the key proteoglycan is aggrecan The central component of aggrecan is a carbohydrate, hyaluronan At 40 nm intervals aggrecan core proteins are attached (assisted by a linker protein) to a decasaccharide sequence in hyaluronan Attached to the aggrecan core protein are multiple GAGs (via the trisaccharide linker) The GAGs in aggrecan are chondroitinsulphate and keratin sulphate MW of an aggrecan 2 x 10 8



127 PROTEOGLYCANS ON THE CELL SURFACE A typical example is syndecan The core protein spans the membrane with a short cytosolic domain The GAGs are attached via the trisaccharide linker to serine residues The GAGs in syndecan are heparan sulphate chains Syndecan binds extracellularly to collagens and fibronectin and intracellularly to the cytoskeleton




131 DISEASES OF GAG Rare genetic defects in enzymes required for the synthesis of Dermatan sulfate lead to defects in bones, joints, muscles, and skin. The individuals do not grow to normal hight and appear prematurely aged.



134 NEURONAL CELL ADHESION MOLECULES LEARNING AND MEMORY Male humans with L1-mutations develop –Mental retardation –Hydrocephalos –Adducted thumbs NCAM knock-out animals develop –Morphological changes in bulbus olfactorius and hippocampus –Impaired learning –Emotional disturbances Modulation of NCAM and L1-function interferes with LTP and learning and memory

135 CELL-MATRIX ADHESION Integrins Collagens Laminin and Fibronectin Proteoglycans and Glucosaminoglycans

136 CELL MATRIX ADHESION Integrins on the cell surface mediate cell-ECM binding Integrins are composed of an - and a - chain There are 3 different -chains and more than 10 types of -chains The chain composition determines the ligand specificity The affinity is generally low (Kd )

137 INTEGRINS Integrins can be activated through a signal from the interior of the cell Activation involves conformational changes of the integrin Various integrins recognize specific sequences in their ligands. E.g. 4 1 recognizes EILDV (in VCAM-1 and in fibronectin) and 5 1 recognizes RGD in many ECM proteins

138 INTEGRIN CONTAINING JUNCTIONS A junction consists of an exterior ligand, a transmem- brane protein, a linker, and a cytoskeletal component An adherence junction connects an ECM component with an integrin linked to an adapter (e.g. vinculin) and F-actin A hemidesmosome connects an ECM-component to integrin and via an adapter (e.g. plectin) to intermediate filaments (keratins)

139 INTEGRIN DISEASES Genetic defects in integrin 2 lead to leucocyte-adhesion deficiency. The patient becomes susceptible to bacterial infections

140 DISINTEGRINS Disintegrins contain the RGD sequence and interfere with integrin-ECM adhesion allowing deadhesion and cell migration The ADAMs (A Disintegrin And a Metalloprotease) remodel surface proteins; f.x. at the fusion of sperm and egg, the fusion of myoblasts during myogenesis, release of TNF from the surface

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