ECM and cell adhesion

Question 1

contributions of ECM to cell and tissue fuction

Answer 1

It is a proteinaceous material secreted by cells. The matrix varies from tissue to tissue creating environments specific for the survival of the cells present

Question 2

4 major classes of ECM components

Answer 2

glycosaminoglycans, fibrous proteins, multidomain adapter proteins, water and solutes

Question 3

glycosaminoglycans (GAGs)

Answer 3

polysaccharide made of disaccharide repeats of N-acetyl-glucosamine (often sulfated) and uronic acid (glucoronic acid). Sulfation and carboxyls give a (-) charge, have extended conformations, fill large volumes relative to mass, and readily form gels.

Question 4

common GAGs

Answer 4

hyaluronan, chondroitin sulfate, dermatan sulfate, heparan sulfate, and keratan sulfate

Question 5

Proteoglycans (PGs)

Answer 5

covalently linked complex of GAGs and protein. Core protein attached to serines special link tetrasaccharides that serve as primers for polysaccharide assumbly. Likely play an important roles eg filtering function of kidner glumerulus and as reservoirs of growth factors and proteases (may bind and modify activity). can be membrane bound via rtransmembrane protein tail or linked via GPI anchor. form highly ordered aggregates

Question 6

fibrous proteins

Answer 6

includes collagen and elastin. Collagens: most abundant proteins in mammals (25% of protein mass). 25 subunits form 20 different collagens. Collagen I is the most common form abundant in connective tissues, Collagen IV is characteristic of basal lamina. Elastin: important property of many tissues provided by a network of elastic fibers in the ECM.

Question 7

multidomain adapter proteins

Answer 7

fibronectin, laminin and tenascin.

Question 8

Fibronectin

Answer 8

dimeric glycoprotein, subunits linked by disulfide bonds, folded into functionally distinct binding domains, repeated smaller modules make up domains, main being type III fibronectin repeats of Arg-Gly-Asp (RGD) binding seq (binds integrins). also bind collagen, heparin, or serve self-association. highly insoluble

Question 9

Laminin

Answer 9

3 subunits (alpha, beta, gamma), asymmetric, disulfide linked cross with longer arm formed by helical structure containing long stretches of all 3 subunits. Found in basal lamina only. Many can self-assemble into network via interactions between ends of arms. also have numerous binding sites

Question 10

“matrix metalloproteases” MMPs

Answer 10

“eat up ECM” allow cell migration and facilitate cell signaling. Important in development of tissures and used by pathogens to invade tissues. Can unmask cryptic cell binding sites promoting cell binding or migration, promote cell detachment, activate growth factors, release ECM bound extracellular signals, highly regulated, and can be specific

Question 11

cell adhesion molecules CAMs

Answer 11

Cadherins, Ig Superfamily (IgSF), and Integrins

Question 12

Cadherins

Answer 12

holodimer, dimerized transmembrane protein, binds calcium, connected to p120, alpha, and beta cetenins within the cytosol which connects them with the actin cytoskeleton. Bind to other cells via cadherins on next cell in a zipper-like fashion.

Question 13

IgSF

Answer 13

look similar to cadherins, small or no cytosolic motif, outside motifs form homodimer between 2 cells, found in nervous system, Ankyrin crosslinks cytoskeleton to the CAMs and binds factors within cells to start signaling.

Question 14

Integrins

Answer 14

heterodimer, alpha and beta subunits, form matrix binding site, connected to actin cytoskeleton by alpha actin, talkin, or filamin. Recycled during cell motility, important for connecting surfaces, important drug target due to role in metastasis and signaling pathways. bind to laminin, fibronectin, and collagen

Question 15

CAMs and cell signaling

Answer 15

assembly of adhesion sites requires action of protein tyrosine kinases, disassembly and detachment requires protein kinase C activity. Rho family GTPases (F-actin polymerization) are associated with certain CAMs. CAMs paired on cytoplasmic face with complex protein assemblies. adhesion sites play major roles in cell differentiation/development and cancer

Question 16

ECM and disease

Answer 16

Collagen I mutations = interfere with osteogenesis and skeletal dysplasia, Fibronectin null mice = early embryonic lethal, laminin mutaitons = nephrotic syndrome (glomerular filtration defect) and neuromuscular juction/muscular innervation problems. MMP 2 or 13 mutations = inherited osteolysis/arthritis syndromes and bone dysplasia. overexpression of MMPs = poor prognosis in cancer

Question 17

cell adhesion and disease

Answer 17

loss of function of CAM may result in embryonic lithality. 2 twos of leukocyte adhesion deficiencies: type I, affecting a particular integrin; type II, affecting selectin (leukocyte rolling)