Block2 9.extracellular Matrix

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Functions of the ECM

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Stabilize the physical structure of cells. Molecular barrier to cell migration during infection and metastasis. Resevoir for growth factors (they are released when it is damaged). Signals to the cell interior during morphogenesis, wound healing, and maintenance of the differentiated state (cells is a culture of synthetic ECM will not de-differentiate).

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Components of the ECM

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Fibrous protein
•Collagens (white connective tissue)
•Elastins (yellow connective tissue)
•Keratins (in nails and hair)
Hydrated gel
•Hyaluronic acid, proteoglycans, specialized ground substances
Multiadhesive matrix proteins
•Fibronectin (loose connective tissue)
•Laminin (basal lamina)
•Others (thrombospondin, tenascin, vitronectin, van Willebrand factor, nidogen/entactin)
Cells (fibroblasts, chondrocytes, osteoblasts, etc)

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Perlecan, Laminin, Fibronectin

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Fibrous and multiadhesive proteins

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Glycosaminoglycans (GAG's)

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GAG = the ground substance.
Unbranched polysaccharides composed of repeating disaccharide units (usually a uronic acid and an amino sugar).
Classified according to the amino sugar they contain.
Highly negative, imbibe lots of water, keeps cells happy. Form the porous hydrated gels that make up most of ECM. Collagen and elastin fibers make up the reinforcing fibers enbedded in this "ground substance"

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Proteoglycans

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Most GAG's are covalently linked to a protein core. These conjugates are proteoglycans. They mediate some of the outside-in signals generated by the binding of ligands. Important ones:
Aggrecan, Decorin, Perlecan

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Aggrecan

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Proteoglycan. Located in cartilage. Mechaincal support, forms large aggregates with hyaluronic acid, binds TGF-beta (sequestering of growth factors)

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Decorin

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Decorin = decorations
Proteoglycan. Decorates collagen fibers. Widespread in ECM. Binds to type 1 collagen fibrils and binds TGF-beta

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Perlecan

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Massive proteoglycan. Located in basal lamina. Structural and filtering function in basal lamina

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Multi-adhesive Matrix Proteins

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large molecules with binding site for matrix and another site for cells somehow. Fibronectin,

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Fibronectin - IMPORTANT

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The most abundant of the ECM proteins. From one gene, may have different splice variants. Consists of two nearly identical chains joined by two disulfide bonds near their carboxyl ends. The globular domains have binding sites for different ECM components or for specific receptors on the cell surface. The receptor-binding domain contains tripeptide sequence RGD, which is recognized by fibronectin receptors

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Laminin

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Laminin = lamina
An important component of the basal lamina synthesized by epithelial and endothelial cells; it is the first adhesive matrix protein to appear during development and is important in neuronal development. Mice without it die very early in development (the 8-cell stage?). Laminin-1 is the principal multiadhesive matrix protein of the basal lamina.
At least 8 different genes code for laminin-like proteins.

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Other multiadhesive matrix proteins (have anti-tumor function, it is very bad when they are turned off because cancers can spread more easily

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Thrombospondin, entactin, tenascin, nidogen/entactin and von Willebrand factor are other members of this group of proteins.

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Cell-to-Cell Adhesion proteins

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Transmembrane proteins:
Cadherins, Ig superfamily CAM's = homophilic interactions (interact with eachother on neighboring cell surfaces).
Integrins - bind ECM molecules like fibronectin.
Selectins - look like plant lectins, bind sugars

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Cadherins

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Present in desmosomes, homophilic interaction to make cell-cell adhesions during development

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Ig CAM's

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Important in neuronal development, homophilic interactions. Ig is like half of the immunoglobulin structure.

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Selectins

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Look like plant lectins, bind sugars. Important in leukocyte extravasation.

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Integrins role in inflammation and Nataluzimab

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Modulating the integrin action reduces inflammation. This is done using antibodies (Nataluzimab) to alpha4-integrin, preventing interactions and therefore their signaling. Inflammation goes down.

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Integrins

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Integrins are obligate heterodimers containing two distinct chains, called the α (alpha) and β (beta) subunits.
•In mammals, 19 α and 8 β subunits have been characterized.
•There are many types of integrins, and many cells have multiple types on their surface.
Many integrins recognized relatively short peptide motifs and in general require an acidic amino acid to be present.

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Subunit Structure and Specificity of Mammalian Integrins

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Beta-1 subunit very promiscuous. It can bind many different alphas. A subset of those are for RGD receptors of fibronectins. The fibronectin-integrin interaction is important

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Integrins: Inactive vs. Active

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Many integrins are expressed on the surface of cells in an inactive state, where they do not bind ligands and do not signal.
•Integrins interact with the elements of the extracellular matrix and mediate various intracellular signals.
•They define cellular shape, mobility, and regulate the cell cycle

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Integrin Signaling

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Integrins communicate biochemical and mechanical signals in a bidirectional manner across the plasma membrane.
•Intracellular signals switch integrins into a ligand-competent state as a result of conformational changes in the extracellular domain.
•Binding of extracellular ligands induces, in turn, structural changes that convey distinct signals to the cell interior. The active form is like a chicks legs opened up for lousing, inactive form they're closed up tightly

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Integrins and Rac/Rho/Cdc42

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Signals can be transduced from integrins through the small GTPases Rac/Rho/Cdc42. These signals include cell proliferation, migration, survival, gene transcription. Makes sense as we knew these proteins were key in cell migration already

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Epidermolysis Bullosa

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Although the most common mutation associated with Epidermolysis Bullosa are mutation in the keratin genes, mutations in genes coding for laminin subunits, collagen XVII, α6 integrin, and β4 integrin have also been described in this disease