Lecture 11: Cell Adhesion and Cell Junctions

Multi-cellular Organisms

• How are cells organized into tissues? - cell adhesion and the ECM

• How do cells communicate with each other & with their environment? - cell signaling

• How do cells control their proliferation? - cell cycle control

Tissues - The organizational basis of multicellular life

Tissues are composed of a variety of differentiated cell types and an extracellular matrix

• Structure - the organization of tissues provides mechanical integrity to otherwise squishy cells

• Function - tissue organization allows cells to communicate with one another and to perform specialized functions in a coordinated way

• Requires that cells recognize & bind to one another or the ECM

Tissues in Animal Cells display 2 Architectural Extremes

Epithelial Tissues

• Epithelial sheets line all body cavities. The cells tightly adhere to one another via anchoring junctions. There is limited extracellular matrix and cells themselves bear mechanical stress

Connective Tissues

• mechanical strength and specialized functions provided primarily by the extracellular matrix. Specialized cell types secrete the matrix and form few permanent attachments.

4 Main Types and Functions of Junctions

• Cells form both transient interactions and stable junctions with other cells or the ECM:

  • Anchoring Junctions transmit stresses by connecting cells to other cells or to the matrix, tethered to cytoskeletal filaments inside the cell (adherens and desmosome junctions)

  • Occluding Junctions seal gaps between epithelial cells to make an impermeable barrier

  • Channel-forming junctions are open cytoplasmic passageways between cells (ex. gap junctions)

  • Signal-relaying junctions form to relay signals at sites of cell-cell contact (ex. neuronal and immunological synapses, cell-cell signaling by Delta/Notch, etc.)

Cell Adhesion Molecules (CAMs)

Transmembrane Cell Adhesion Molecules (CAMs) bind cells to other cells or the ECM. In anchoring junctions, they collaborate with intracellular anchoring proteins and cytoskeletal filaments

Cell Adhesion Molecule (CAM) families:

• Cadherins (mainly cell-cell attachment)

• Integrins (mainly cell-matrix attachment)

• Selectins (Transient cell-cell adhesions in the bloodstream)

• Immunoglobulin (Ig)- Superfamily members

CAM- ligand binding is also important in cell-cell signaling

• CAM binding can activate signaling molecules bound to the cytoplasmic domain of the CAM

• Binding of the extracellular ligand activates signal transduction, resulting in changes to gene expression

Cadherins Mediate Ca2+ Dependent Cell-Cell Adhesion in Animals

• 5 extracellular Ca2+ binding domains

• In the presence of Ca2+, cadherins stiffen up

• Several cadherin subtypes, 2 main ones:

  • E-cadherin- epithelial

  • N-cadherin- nerve/muscle

Cadherins Mediate Primarily Homophilic Cell-Cell interactions

• Typically responsible for like-like interactions between similar cadherins on similar cells

• Tissue “sorting out” experiments suggest that such specific mechanisms allow cells of similar types to selectively recognize and adhere to each other

Cadherins are important in embryonic development

• main adhesion molecules holding cells together in embryonic tissue

• Predominant CAM responsible for “sorting out” of embryonic cells

• Cadherins are important in cell junctions in adult tissues

  • epithelial cell junctions

  • adhesion at synaptic junctions

How are tissues formed during development?

• cell division followed by cell adhesion

  • Cell migration and selective adhesion

Cadherins Control the Selective Assortment of Cells

• during embryonic development, as the neural tube pinches off from the ectoderm, the cells in it switch from expressing E-cadherin to N-cadherin, so they can stick together

Cadherins are also important in regulating cell motility

• localization of GFP-E- cadherin as migrating cells contact each other

• Epitherlia/mesenchymal transitions during development

• Tumor cell metastasis

  • most metastatic tumor cells lose cadherin expression

  • forced cadherin expression can reduce the ability of cancerous cells to form tumors

Cadherins form adherens junctions, a type of anchoring junction

• In adherens junctions, intracellular domains of cadherins are linked to the actin cytoskeleton by catenins

Adherens Junctions form adhesion belts across epithelial cell sheets

• Inside the cells, the adherens junctions are connected to contractile bundles of actin filaments (green). This plays an important role in tissue morphogenesis

Desmosomes: another type of anchoring junctions that bind intermediate filaments (keratin)

• desmosomes are rivets that connect to intermediate filaments (keratin) inside cells, making a continuous network joining epithelial cells.

• Desmosomes maintain tissue integrity by providing mechanical strength

Ig Superfamily CAMs: important in immune and neuronal function

• Contain Ig domains found in antibodies and other proteins that function in the immune system

  • Ca2+ independent binding

• Mediate adhesion between endothelial cells and white blood cells - heterophilic interactions between ICAMs and integrins

• N-CAM and L1 are important in nerve outgrowth during development. NCAM participates with homophilic interactions with NCAMs on other cells

  • mutations in L1 cause hydrocephalus (fatal) or mental retardation

Selectins, the sweet-tooth CAM

• Selectins belong to the lectin group of proteins that bind specific sugar residues on cell surface glycoproteins

• Selectins are important in adhesive interactions between lymphocytes and other cells

  • L-selectin- found on leukocytes

  • E selectin- found on endothelial cells

  • P selectin- found on platelets

Example of CAM interactions: Inflammatory response

• Different CAMs cooperate to mediate the transient adhesive and cell signaling interactions that underlie many important physiological responses

  • normally neurophils/leukocytes circulate in blood system

  • in response to tissue damage or infection leukocytes traverse the endothelial blood vessel wall and migrate to the site of trauma

  • There they ingest foreign or damaged cells, producing pain and swelling

1. Tissue damage or infection activates enothelial (blood vessel lining ) cells to display E-selectins

2. Selectins bind to glycoproteins on neutrophil suface; movement of neutrophils slows to a “slow roll”

3. Selectin binding causes endothelial cells to release platelet activating factor (PAF). PAF triggers a signaling pathway in the neutrophil that causes integrins to become activated

4. Neutrophils now adhere strongly to the endothelial wall due to an interaction between the activated integrin and ICAM.

5. Integrin binding signals the neutrophil to change shape and migrate through the endothelial vessel wall

Tight Junctions make an epithelium “leak proof”

Ex: transcellular transport of nutrients (glucose) across gut epithelium

• Tight junctions maintain a diffusion barrier between the lumen of the gut and the interior of the tissue

• Tight Junctions are fences preventing diffusion between apical and basolateral membranes, thereby facilitating glucose transport

Ex. The blood/brain barrier

• blood brain barrier seals the endothelial wall of capillaries in the brain

• immune cells can cross the bbb

Occluding Junctions: a type of tight junctions

Occluding junctions utilize 2-ply quilted construction to form a nice tight seal

• two protein families, the claudins and occludins, stitch the membranes together

• Different TJs have different permeability properties

Communicating Junctions: Gap junctions permit cell-to-cell communication

• GJs present in virtually all cells that make significant contacts

• GJs are formed from connexin proteins (about 20 have been identified)

• 6 connexins form a membrane channel that links to a connexon in the adjacent cell

• GJ permeability can be regulated

Why might you want to share small molecules with your neighbor?

• Coordinated signaling: signaling molecules like cyclic AMP pass through GJs, leading to signal propagation in clusters of cells

• Electrical coupling: GJs allow depolarization of muscle cells to spread rapidly, ensuring synchronous contraction