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Transcript
The Extracellular Space • Epithelial tissues – closely packed cells lining spaces in the body (e.g. skin, intestine, etc) • Connective tissues – Largely composed of non-living extracellular material (e.g. cartilage, tendon, dermis) The Extracellular Space • Proteins in plasma membrane have sugars attached • Glycocalyx – – – – Mediate cell interactions Provide mechanical support Barrier to particles Binding sites for regulatory factors The Extracellular Matrix (ECM) • An organized network of materials located beyond the plasma membrane The Extracellular Matrix (ECM) • Basement membranes – Thick regions of ECM • Surround muscle/fat • Underlie the basal surface of epithelial tissues The Extracellular Matrix (ECM) • Basement membranes – Separate different tissues – Provide mechanical support – Barrier to macromolecule and cellular movement – Substrate for cell migration – Generate signals that maintain cell survival The Extracellular Matrix (ECM) • Collagens (27 different types) – High tensile strength (resistant to pulling forces) – Alpha-helical trimers bundle together into fibrils – Types I, II, III (fibrillar) form rigid cables • Adjacent collagens are strengthened by covalent cross-links – Hydroxylysine - lysine – Type IV (nonfibrillar) can form an interconnected lattice The Extracellular Matrix (ECM) • Collagens (27 different types) – Type IV (nonfibrillar) can form an interconnected lattice • Composed of helical and non-helical segments (flexibility) • Globular domains at each end (lattice contact points) – Collagens bind: • Fibronectins • Integrins (cell surface) The Extracellular Matrix (ECM) • Diseases caused by defects in collagen genes – Osteogenesis imperfecta • Fragile bones – Ehlers-Danlos syndrome • Hyperflexible joints, highly extensible skin The Extracellular Matrix (ECM) • Proteoglycans – Protein core + glycosaminoglycan (GAG) polysaccharide complex • Chondroitin sulfate & keratin sulfate • High amount of negative charge binds cations and H2O • Hydrated gel resists compressive forces – Hyaluronic acid links many proteoglycans to form extremely large molecules – Fill the scaffold created by collagens The Extracellular Matrix (ECM) • Fibronectins – Modular domains for interactions – Bind collagens, proteoglycans, integrins at cell surface – Important for: • linking ECM components together, cell attachment to matrix, cell migration NC cells The Extracellular Matrix (ECM) • Laminins – 3 polypeptides linked by disulfide bonds – Form a second lattice interwoven with Collagen IV lattice – Bind to proteoglycans, integrins at cell surface PGC on laminin ECM Remodeling • Matrix metalloproteinases (MMPs) – Enzymes that degrade ECM proteins – Tissue remodeling – Cell migration – Wound healing Steps leading to metastatic spread MMP activity Cell - ECM Interactions • Integrins – Only found in animals – Heterodimer of alpha and beta subunits • 18 alpha and 8 beta subunits known • 12 different alpha/beta combinations known – Transmembrane proteins • Extracellular domain, transmembrane domain, intracellular domain • Inside-out signaling – Post-translational alterations to cytoplasmic tail regulate conformation changes in extracellular domain – Talin separates beta from alpha to open receptor to active state Plasma membrane talin Inactive Active Cell - ECM Interactions • Ligand binding – RGD loop of Fibronectin binds to integrin receptor extracellular domain – Isolated RGD Loop can be exploited to block platelet aggregation / blood clotting Cell - ECM Interactions • Integrins – Two major functions • Adhesion to substrate – Receptors cluster increasing overall strength • Signal transmission – Binding of ligand (collagen) can change cytoplasmic domain – Cytoplasmic domain can activate kinases such as FAK and Src – Activated kinases can transmit signals to nucleus and change gene expression Cell - ECM Interactions • Structures important for adhesion to substrate – Focal adhesions: • Scattered, discrete, transient, dynamic, rapidly form and break • Clusters of integrins bound to collagen / Fibronectin • Cytoplasmic domains attach to cytoskeleton connecting exterior forces to internal signals – Actin filaments – Focal adhesion kinase (FAK) Forces exerted by focal adhesions Cell - ECM Interactions • Structures important for adhesion to substrate – Hemidesmosome • more permanent anchor to basement membrane • Integrins bound to laminin to dense collection of intermediate filaments Cell - ECM Interactions • Structures important for adhesion to substrate – Hemidesmosome • Disease: epidermolysis bullosa – Epidermis poorly connected to basement membrane / dermis – Fluid accumulates in between = blister Epidermolysis Bullosa Type Genes Mutated Simplex Junctional Dystrophic Keratin-5; Keratin-14; plectin laminin-5; collagen XVII; a6b4 integrin collagen VII (keratins) Cell - ECM Interactions Cell - Cell Interactions • Cadherins: Ca2+ dependent adhesion – Homophilic interactions allow self-sorting of mixed cell populations – Disease role: metastasis of cancer • Lose adhesion by downregulating cadherin expression • Penetrate / invade barriers by upregulating MMP expression Cell - Cell Interactions • Structures important for cell-cell adhesion – Adherens junctions (30nm gap between cells) • Cadherin-cadherin interactions in belt-like strips holding two cells together • Cytoplasmic domains link via beta-catenin and alpha-catenin to the cytoskeleton Cell - Cell Interactions • Structures important for cell-cell adhesion – Desmosomes (1 um diameter disc) • Resist mechanical stress • Cadherin-cadherin interactions linked to cytoskeleton (intermediate filaments) Cell - Cell Interactions • Tight junctions – Seal two membranes together – Block paracellular movement – Occludin and claudins (24 genes) – Different claudins have different permeabilities • #1 doesn’t allow H2O to pass, #16 is permeable to Mg2+ • Important for maintaining blood-brain barrier Cell - Cell Interactions • Gap junctions – Join cytoplasmic spaces between adjacent cells via a narrow pore • 1.5nm diameter • 1kD cutoff, small molecules freely pass (ATP, cAMP, Ca2+, etc) – Subunits are connexins – Open / close regulated by phosphorylation – Integrates cells of a tissue into a functional unit Cell - Cell Interactions Plant cell-cell interactions • Plasmodesmata – Join adjacent plant cytoplasmic spaces – Capable of dilation, 1kD cutoff can open to a 50kD cutoff – Exploited by some plant viruses Roles of the plant cell wall • Cell wall functions – Structural role supporting and protecting plant cells • Cellulose microfibrils confer tensile strength – Signaling roles • Cell wall-associated transmembrane protein kinases – Dynamic not static, undergoes significant remodeling