Biology 416- Signaling- Cell Junctions 4/1/08

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TGFB

Transcription Factor:
Mechanism of Transcription Factor Activation:

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Transcription Factor: Smads
Mechanism of Transcription Factor Activation: Phosphorylation in cytosol by activated receptor

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Cytokine Receptors

Transcription Factor:
Mechanism of Transcription Factor Activation:

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Transcription Factor: STATs
Mechanism of Transcription Factor Activation: Phosphorylation in cytosol by JAK kinase

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Receptor Tyrosine Kinases (RTKs)

Transcription Factor:
Mechanism of Transcription Factor Activation:

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Transcription Factor: Various
Mechanism of Transcription Factor Activation: Phosphorylation by cytosolic kinase in nucleus or cytosol

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G Protein Coupled Receptors (GPCR)

Transcription Factor:
Mechanism of Transcription Factor Activation:

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Transcription Factor: CREB
Mechanism of Transcription Factor Activation: Phosphorylation in nucleus by protein kinase a

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Wnt Receptor

Transcription Factor:
Mechanism of Transcription Factor Activation:

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Transcription Factor: B- Catenin
Mechanism of Transcription Factor Activation: Disassembly of multiprotein complex in cytosol; acts with transcription factor in nucleus

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Hedgehog Receptor

Transcription Factor:
Mechanism of Transcription Factor Activation:

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Transcription Factor: Ci (activator; Ci fragment (repressor)
Mechanism of Transcription Factor Activation: disassembly of multiprotein complex in cytosol

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TNF-alpha Receptors

Transcription Factor:
Mechanism of Transcription Factor Activation:

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Transcription Factor: NF-KB
Mechanism of Transcription Factor Activation: phosphorylation and degradation of inhibitor of NF-KB in cytosol

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Notch (delta receptors)

Transcription Factor:
Mechanism of Transcription Factor Activation:

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Transcription Factor: Notch cytosolic domain
Mechanism of Transcription Factor Activation: Proteolytic release of Notch cytosolic domain, which acts with nuclear transcription factors

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NF-kB signaling pathway

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Resting cells - NF-kB dimer bound to inhibitor.
Numerous stresses can activate I-kB kinase.
Phosphorylated I-kB binds ubiquitin ligase (E3).
Polyubiquitinated I-kB  proteasome.
NF-kB released.
NLS on NF-kB subunits exposed  translocation of NF-kB to nucleus.
NF-kB activates transcription of specific genes, including I-kBa.

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What agents stimulate NF-kB signaling pathway?

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Bacterial, fungal, and virus infection, binding of cytokines to receptors, ionizing radiation, etc.

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Notch/Delta signaling pathway

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Notch binds Delta on adjoining cell membrane.
Matrix metalloprotease (ADAM 10) cleaves extracellular region of Notch.
g-secretase cleaves Notch within the membrane, releasing cytosolic Notch.
Cytosolic Notch segment translocated to nucleus - interacts with transcription factors.

Important in determining cell fate during development.

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Tight junctions

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function: controlling solute flow, signaling

adhesion proteins connect cells, interact with adapter proteins, connect to the cytoskeleton. Control flow of solutes through extracellular spaces between cells

are the closely associated areas of two cells whose membranes join together forming a virtual impermeable barrier to fluid.

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Gap junctions

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Function: Communication; small-molecule transport between cells

allow diffusion of small water-soluble materials between adjacent cells.

a junction between certain animal cell-types that allows different molecules and ions, mostly small intracellular signaling molecules (intracellular mediators), to pass freely between cells. The junction connects the cytoplasm of cells. One gap junction is composed of two connexons (or hemichannels) which connect across the intercellular space.

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Microvilli

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structures that increase the surface area of cells, and are involved in a wide variety of functions, including absorption, secretion, cellular adhesion, and mechanotransduction.

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Adherens junctions

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Function: Shape, Tension, Signaling

connect lateral membranes, interact with a belt of actin and myosin filaments, internally bracing the cell

protein complexes that occur at cell-cell junctions in epithelial tissues, usually more basal than tight junctions.

They can appear as bands encircling the cell (zonula adherens) or as spots of attachment to the extracellular matrix (adhesion plaques).

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Spot desmosomes

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a cell structure specialized for cell-to-cell adhesion. A type of junctional complex, they are localized spot-like adhesions randomly arranged on the lateral sides of plasma membranes.

Desmosomes help to resist shearing forces and are found in simple and stratified squamous epithelium. The intercellular space is very wide (about 30 nm).

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Hemidesmosomes

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shape, rigidity, signaling

mostly on basal surface, connecting epithelium to extracellular matrix - also transfer shear forces

very small stud- or rivet-like structures on the inner basal surface of keratinocytes in the epidermis of skin. They are similar in form to desmosomes. While desmosomes link two cells together, hemidesmosomes attach one cell to the extracellular matrix. Rather than using cadherins, hemidesmosomes use integrin cell adhesion proteins. Hemidesmosomes are asymmetrical and are found in epithelial cells connecting the basal face to other cells.

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Cell-cell adhesion:

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Cell adhesion molecules (CAMs) bind to CAMs on adjacent cells.

Protein-protein interactions

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Cell-matrix adhesion:

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Adhesion receptors bind components of ECM.

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How can cells distinguish between self and non-self?

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Cell adhesion molecules

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What does blocking function or expression of ECM proteins do?

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blocks development in specific ways

Block fibronection action with antibodies  block branching during morphogenesis in mouse tissues.

Block collagen or perlecan gene activity (using null mutants)  defects in cartilage and bone development.

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Epithelia

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sheetlike coverings of tightly-linked cells on external and internal body surfaces

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What does the phrase, "epithelial cells are polarized," mean?

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have distinct apical, basal, and lateral surfaces.

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How are cells held together?

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Held together by anchoring junctions and tight junctions. Also contain gap junctions.

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Anchoring junctions

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Anchoring junctions - Also interact with adapter proteins and cytoskeleton. Include:
Adherens junctions - connect lateral membranes, interact with a belt of actin and myosin filaments, internally bracing the cell
Desmosomes - connect lateral membranes, spot-welds cells together - transfer shear forces to the epithelium as a whole, strengthening it
Hemidesmosomes - mostly on basal surface, connecting epithelium to extracellular matrix - also transfer shear forces

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Desmosomes

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contain a cytoplasmic plaque and intermediate filaments

Desmosomes connect to cytoskeletal intermediate filaments

Function: strength, durability, signaling

connect lateral membranes, spot-welds cells together - transfer shear forces to the epithelium as a whole, strengthening it

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Plasmodesmata

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Adhesion Type: Cell to Cell
Cytoskeletal Attachment: Actin Filament
Function: Communication; Molecule transport between cells

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What are the typical protein constituents of adherens junctions?

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-e-cadherin
-alpha-catenin
-beta-catenin
-ZO1
-VASP
-Vinculin
-p120-catenin

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What does cadherin do?

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cells clump in the presence of calcium.

Normal differentiation - cadherin expression declines when non-motile epithelial cells  motile mesenchymal cells.

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How can you measure the diameter of the gap-junction channel?

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by observing whether various fluorescent dyes pass into neighboring cells.

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Integrins

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CAMs and adhesion receptors