Cell and Molecular Biology Gerald Karp Cell and Molecular Biology Fifth Edition CHAPTER 7 Part 1 Interactions Between Cells and Their Environment Copyright © 2008 by John Wiley & Sons, Inc.

7.1 The extracellular space Glycocalyx (cell coat): cell-cell interaction cell-substratum interaction

The extracellular matrix (ECM) plays a regulatory role in determining the shape and activities of cells a. Collagen b. Proteoglycans c. Fibronectin d. laminin

Best-defined ECM Basement membrane (basal lamina): a continuous sheet 50-200 nm thick that (1) surrounds muscle and fat cells (2) underlies the basal surface of epithelial tissues or the lining of the digestive and respiratory tracts (3) underlies the inner ECs of blood vessels

a. Collagen (fibrous glycoprotein) Found throughout in animal kingdom High tensile strength, that is, their resistance to pulling forces is strong A collagen fiber 1 mm in diameter is capable of suspending a weight of 10 kg without breaking. Is the single most abundant protein in human body (25%)

Collagen (Cont.) Is produced primarily by fibroblasts, smooth muscle cells and epithelial cells More than 20 distinct types of collagen have been identified All share at least two structural features: trimers of α chains and wound around each other to form a rod-like triple helix

Tendons : connect muscle and bone Stroma of cornea: transparency Type I collagen gene mutation: thin skin, death Type II mutation (cartilage tissue): skeletal deformaties Other mutations: hyperflexible joints, highly extensible skin

b. Proteoglycans (protein-polysaccharides complex)

The GAG chains also act as binding sites for many growth factors, affecting their interaction with cell-surface receptors GAG “-” H3O ”+” Hydrated gel with pores resists crushing forces Collagens and GAGs give cartilage and other ECM strength and resistance to deformation.

c. Fibronectin

d. Laminin Three different polypeptide chains connected by S-S bonds Long arm and short arm Effect on cell migration and cell differentiation (laminin receptor on cell surface) i.e. guiding tips of embryoic axons, migration of primordial germ cell

Matrix metalloproteinases (MMPs) Zinc containing proteins either secreted into the extracellular space or anchored to the plasma membrane Tissue remodeling Migration Wound healing Angiogenesis

Athritis Atherosclerosis Hepatitis Tooth and gum diseases Tumor progression

7.2 Interactions of cells with extracellular materials Integrins (membrane receptors) Focal adhesions and hemidesmosomes: anchor cells to their substratum αβ chain spans membrane, non-covalently linked, 17α,8β, 20+ kinds of integrins (Fig. 7.5)

Integrin (cont.) Large extracellular portion Small cytoplasmic portion Ca2+ binding site on αchain βchain can recognize RGD sequence on fibronectin, activate FAK pathway

Change in conformation of the cytoplasmic domains, increasing the integrin’s affinity for an extracellular ligand “Inside-out” theory The aggregation of platelets during blood clotting occur only after the cytoplasmic activation of αIIbβ3 integrins which increases their affinity for fibrinogen

“Outside-in” signaling Integrin binds to fibronectin or collagen Conformational changes at the cytoplasmic end of the integrin FAK Protein phosphorylation Nucleus (cell division, differentiation, motility, growth, survival, cancer cells vs. normal cells)

Integrins link ECM to cytoskeletons Focal adhesion (in vitro with actin) Hemidesmosomes (in vivo with keratin, IF) Out-side-in Normal cells (integrin dependent) and malignant cells (integrin independent)

Bullous pemphigoid Individual’s bp proteins (autoantibodies) present in these adhesive structures. These autoantibodies cause the lower layer of the epidermis to lose attachment to the underlying basement membrane. The leakage of fluid into the space beneath the epidermis results in severe blistering of the skin. Epidermis, GI, urinary tracts

7.3 interactions of cells with other cells Cells can recognize the surfaces of other cells Interacting with some and ignoring others

Little was known about the nature of the molecules that mediate cell-cell adhesion until The development of techniques for purifying integral membrane proteins The isolation and cloning of genes that encode these proteins

Four distinct families of integral membrane proteins play a major role in mediating cell-cell adhesion Cell-cell adhesion molecules 1. Selectins 2. Certain members of IgSFs and integrins 3. Cadherins 4. Adherenes junctions and desmosomes: anchoring cells to other cells

1. Selectins LEU-CAM1 (L-selctins) in vivo: lymphocytes homing A family of intergral membrane glycoprotein Bind to the oligosaccharides of other cells Possess a small cytoplasmic domain and a large extracellular segment Role of selectins in inflammation (P.263)

2. Immunoglobulins and integrins Ig domains: 70-100 amino acids Most IgSF mediate lymphocytes and macrophages and target cells for immune response Calcium-independent cell-cell adhesion Some IgSF such as VCAM, NCAM and L1 mediate interaction between nonimmune cells i.e. nerve outgrowth, synapse formation, nervous development Deformed babies due to L1 mutation, water on the brain, mental retardation Integrins α4β1 binds to VCAM on blood vessels

3. Cadherins Transmit signals from ECM to the cytoplasm Mediate Ca2+-dependent cell-cell adhesion E-cadherins, N-cadherins, P-cadherins

4. Adherins junctions and desmosomes: anchoring cells to other cells Adhesive junctions (ca2+dependent): 1.adherens junctions 2.desmosomes 3.junctional complexes (tight junction and gap junction)