Interactions between cell and the environment

Proteoglycan functions

1. Resists crushing forces 2. Cushions cells 3. Provide binding sites for growth hormones to protect from proteases. 4. Regulate division of small signaling molecules in a developing embryo

3 Parts of Selectins

1. Small cytoplasmic domain 2. Single membrane-spanning domain 3. Large extracellular segment

Collagen mutations (4 types)

1. Type I (osteogenesis imperfecta "fragile bones") 2. Type II (dwarfism spondyloepyphesial dysplasia 3. Diverse collagens (Ehler-Danlos syndromes "hyperflexibility") 4. Type IV non-fibrillar (Alpert syndrome: kidney disease of the glomerular basement protein)

3 IgSF molecules

1. VCAM: Vascular cell-adhesion molecule 2. NCAM: Neural cell-adhesion molecule 3. L1: Neural devlopment

Connexon

A complex of organized connexins. Adjacent cell connexons create a single gap junction

Tight Junctions (TJs)

Specialized contacts between epithelial cells. Located apical to junctional complex between adjacent cells. Serve as a barrier to free diffusion of water and solutes both into and out of the tissue that epithelia surround. Some are permeable to specific ions or solutes.

Cell migration during embryogenesis

Specific fibronectin and laminin proteins are recognized by receptor proteins on migrating cell surfaces and followed to the appropriate destination. Eg. migrating neural crest cells that differentiate as pigment cells and facial/bone cartilage that follow fibronectin tracks.

2 Functions of Integrins

1. Anchoring 2. Signaling

4 unique metastatic cell adhesion properties

1. Are less adhesive (cadherins) 2. No longer anchorage dependent (integrins) 3. Are able to penetrate several barriers (MMPs) 4. Are able to invade normal tissues (MMPs, EMTs)

Collagen fun facts

1. Are the most abundant proteins in the human body. 2. About 27 distinct types encoded by the human genome. 3. Each is restricted to a particular tissue.

3 major tissue types

1. Connective 2. Muscle 3. Neuronal

3 main Cadherin glycoproteins

1. E-cadherin: epithelial 2. N-cadherin: neural 3. P-cadherin: placental

3 Types of Selectins, all calcium-dependent

1. E-selectin: on endothelial cells. 2. P-selectin: on platelets and endothelial cells. 3. L-selectin: on white blood cells.

Collagen structure

1. ECM contains heterogeneous mix of different collagens and trimers can be homo- or heterotrimeric, producing diversity in functional properties. 2. Different structural arrangements contribute to uniquely to functional properties. 3. Tendon collagen is aligned parallel to the long axis of the tendon to give tensile strength in the direction of the pulling forces. 4. In the cornea, stratified, perpendicular layers provide rigidity and structural protection, while uniformity in size and distribution minimizes scattering of incoming light.

Collagen functions

1. Establish an insoluble framework that determines the mechanical properties of the matrix. 2. Prolines and lysines are heavily hydroxylated by specific enzymes allowing crosslinking via H-bonds, stabilizing the trimer. 3. Several types assemble into long, rigid, cable-like fibrils, strengthened by covalent crosslinks between lysines.

3 Main components of ECM

1. Long, fibrous proteins that form a mesh-like network surrounding the cell 2. Highly glycosylated proteoglycans that cushion the cell 3. Transmembrane proteins that are connected to these extracellular molecules and respond to both mechanical and chemical signals.

5 Functions of Basal Lamina

1. Maintains cell attachment. 2. Provides signals for cell survival (usual contact dependent) 3. Separate distinct tissues in an organ 4. Serves as substratum for cell migration 5. Forms a barrier to macromolecules

2 Main TM proteins

1. Occludins 2. Claudins

Beta-catenin

A key element in a signaling pathway that leads from the cell surface to the cell nucleus.

Tunneling nanotubes (cytonemes)

A new type of communication where protrusions that extend from the plasma membrane enable different animal cells to touch over long distances. Research suggests these long narrow membrane enclosed tubes deliver some signaling molecules between cells (as opposed to the signals being released into the extracellular space and diffusing to the target cell).

Hyaluronic acid

A non sulfate GAG that forms a giant complex when crosslinked to proteoglycans.

Keratin

A protein that makes up hemidesmosomes along with intermediate filaments. Makes up a dense plaque. Keratin filaments are linked to the ECM by membrane-spanning integrins that anchor the hemidesmosme to the ECM via interactions with laminin.

Metastasis

Abnormal cell proliferation from a secondary tumor, more dangerous than those from primary tumor. This is due to their ability to spread.

Inside-out signaling

Activation of a number of cytoplasmic ligands binds the cytoplasmic tails and separates the alpha and beta chains. This induces a conformational change that allows integrin to bind ECM ligands. Promotes strong interactions between cells and ECM.

Laminin

Along with fibronectin play roles as road maps for migrating cells during animal development.

Basement membrane

Also known as the basal lamina. Specialized ECM under basal surface of epithelia. Is a continuous sheet.

Extracellular matrix (ECM)

An organized network beyond the plasma membrane that plays key regulatory roles in determining cell shape and activities. Regulates diffusion of ligands and their interactions with receptors, playing a key role in cell signaling.

Integrins

Animal-specific transmembrane heterodimers made of distinct alpha and beta subunits. There are about 18 alpha and 8 beta subunits which generate diverse heterodimers with different ligand specificity. An inactive integrin dimer sits at the cell surface in a bent conformation incapable of interacting with ECM proteins.

Disease states associated with MMPs

Arthritis, blood clots, gum disease, heart attacks. Malignant tumor cells require MMP expression, allowing invasion (metastasis) into other tissues.

Fibroblasts

Resident cells that are largely autonomous, non-connected, and motile.

Type IV collagen network

Basement membrane from human amniotic tissue shows an irregular, polygonal lattice. Is non-fibrillar.

Thrombosis

Blood clots which occur when platelets adhere to one another through fibronogen bridges that bind to platelet-integrins. Antithrombotic drugs have been developed that are synthetic RGD peptides. These peptides target integrins on platelets (in this case, thrombocytes) and prevent platelets from binding to fibronogen (blood plasma protein).

Glycocalyx

Cell coat. A glycoprotein-polysaccharide covering that surrounds the cell membranes of epithelial cells. Mediates cell-cell and cell-substratum interactions, provides mechanical protection to cells, and inhibits movement of extracellular material towards the plasma membrane. Facilitates the binding of important signaling molecules to the cell surface.

ECM and contact dependency

Cell survival is ECM contact dependent, which is mediated via integrin signaling. Most cancer cells have lost this anchorage dependency and can exist without ECM contact dependency.

Cell-Cell Interaction

Cells have cell-type specific surface recognition proteins that maintain tissue organization. Eg. selectins, integrins, cadherins, immunoglobulins.

Connective tissues

Consist of mostly extracellular material secreted by the resident cells.

Dynamic properties of ECM

Constant remodeling by degradation and reconstruction. ECM materials degraded by MMPs secreted by migrating fibroblast cells.

GAP junctions

Created by a cluster of connexons in adjacent cells. Molecules up to 1000 Da can pass through. Play an important role in ion passage allowing muscle cells to contract synchronously.

Integrin Anchoring

Critical for adhesion of cells to their substratum or to other cells.

Plasmodesmata

Cytoplasmic channels passing through cell walls of adjacent plant cells. Plant cells are separated by impermeable cellulose rich cell walls.

RGD (arginine-glycine-aspartic acid)

Extracellular proteins that interact with integrins. These interactions have led to new drug treatments of human disorders such as thrombosis, MS, and Crohn's). These drugs work by inhibiting the reactions between specific integrins and their target substrates.

Desmosomes

Disk-shaped adhesive junctions between cells. Found in a variety of tissues subject to mechanical stress (eg. skin, heart, cervix). Contains cadherins (desmocollin and desmoglein) that link the two cells across a narrow gap. Linked to distinct cytoskeletal proteins (intermediate filaments).

Collagen-based diseases

Diverse causes to collagen-containing scar tissue that replaces normal connective tissue such as in pulmonary fibrosis and liver cirrhosis.

Focal adhesions

Docking sites where cells adhere to their substratum and send signals to the cell interior. Cytoplasmic domains of integrins contain binding sites for a variety of cytoplasmic proteins. Relay chemical and mechanical information to the cell interior, altering the cytoskeleton dynamics and gene expression. Can be rapidly assembled/disassembled in order to promote cell migration.

Mesnechymal cell

During embryogenesis, cells gain and lose specific adhesive properties allowing cells to dissociate from the epithelium and migrate dependently.

Proteoglycan structure

Each GAG chain consists of a repeating disaccharide structure. Extremely acidic due to presence of carboxyl and sulfate groups. Negatively charged GAGs attract lots of cations, which in turn attract H20 forming a porous, hydrated gel (providing a cushion in connective tissue).

Fibrosis

Excessive production of collagen-containing connective tissue.

Outside-in signaling

Extracellular ECM ligands (primarily fibronectin and collagen) can bind sites in some integrin dimers inducing conformational change.

Integrin Signaling

Major role in integrating extracellular and intracellular environments. Can signal both from extracellular to cytoplasm and from cell to ECM.

Fibronectin

Facilitates interactions between ECM components. Contains two polypeptides joined by disulfide bonds. Each one contains about 30 distinct Fn globular modules arranged in 5-6 domains. Single human gene produces several protein isoforms through alternative splicing. Along with collagen and proteoglycans, enhances ECM framework.

Selectins

Family of integral member glycoproteins that recognize and bind specific glycosylation patterns on cell surface proteins. Mediate transient interaction between migrating white blood cells (leukocytes) and blood vessel walls at a site of inflammation.

Collagen composition

Fibrous glycoproteins only found in the ECM. Each molecule is a triple helix of 3 helical alpha chains. Bundled together to form large collagen bundles. Secreted principally by fibroblasts. All collagens are trimers of helical chains wound around each other.

Adherens junctions

Form "belts" near apical surface. Junctional complexes promote tight cell-cell contact.

Tissues

Formed when cells interact physically and chemically with one another and extracellular material.

Integrins and Fibronectin

IM receptor proteins that hold the ECM in stable attachment to the cell. Fibronectin transmits mechanical force as signals attached to cells which relay this info to the cell interior for responses via the integrin receptors.

Cadherins

Large family of glycoproteins that mediate Ca2+ dependent cell-cell adhesion. Join cells of similar type to one another (preferentially bind same cadherin on neighboring cells). Involved in transmitting signals from the ECM to the cytoplasm.

Effects of Outside-in signaling

Leads to cytoplasmic interactions with diverse proteins affecting: 1. Cytoskeletal dynamics: Promoting formation of focal adhesions and hemidesmosomes. 2. Change in cell shape, motility 3. Cytoplasmic signaling cascades (leads to gene activation/deactivation) 4. Secretion of signaling molecules from other cells

ECM composition

Made of fibrous proteins and proteoglycans that are secreted by and surround all cell types. Involved in regulating diverse cell physiology including cell-cell contact, proliferation, migration, cell signaling, gene expression and differentiation.

Epithelial-Mesenchymal Transition (EMT)

Mediates many of the changes in adhesive contacts during embryonic development. Regulates the expression of cadherins in order to undergo EMT and migrate to new positions or partition a developing epithilium into distinct tissues.

Immunoglobulin Superfamily (IgSF)

Mostly involved in immune function, however some mediate calcium-independent cell reactions. Promote axonal guidance during neural development. Defects in their function can cause developmental challenges involving the spinal column failing to close properly (eg. spina bifida and hydrocephaly).

Gap junctions

Open channels between animal cells that allow cytoplasmic sharing and intercellular communication.

Actin filaments

Part of the cytoskeleton that links proteins (including beta catenin) in order to connect to cytoplasmic domains of cadherin molecules.

Matrix metalloproteinases (MMPs)

Promote tissue remodeling during embryogenesis, embryonic cell migration, wound healing, and blood vessel formation.

Proteoglycans

Protein-polysaccharide complexes, with a core protein connected to long chain GAGs (gycosaminoglycans). Often taken as a supplement to improve skin and joint conditions.

Connective tissue diseases

Result from improper collagen folding. For example, scurvy results from Vitamin C (ascorbic acid) deficiency preventing proline hydroxylation and collagen processing. Causes poor wound healing, inflamed gums, tooth loss, brittle bones, and damaged blood vessels.

Hemidesmosomes

Rivets that promote basal attachment of epithelial cells to the basement membrane. Actin cytoskeleton supported docking sites with the ECM and other cells.

Epithelia

Sheets of closely packed cells connected tightly to one another and the basement membrane (a defined extracellular material). It forms a barrier that lines both the external surface and the internal cavities and lumina of tissues (eg. epidermis).

Connexin

TM protein. 6 copies in each gap junction channel.