Cell Junctions - 1

MEDICAL CELL BIOLOGY

November 12, 2010

CELL JUNCTIONS AND CELL ADHESION

Michael D. Henry, Ph.D.Department of Molecular Physiology and Biophysics

6-510 BSB, 335-7886 michael-henry@uiowa.edu

RECOMMENDED READING: Alberts et al., Molecular Biology of the CellChapter 19: pp 1131-1162, 1169-1178

KEY CONCEPTS:

1. Cell junctions are relatively permanent and strong sites of cell-cell and cell-ECM attachment.

2. There are four classes of cell junctions: anchoring, occluding, channel-forming and signal-relaying junctions.

3. Anchoring junctions associated with intermediate filaments (desmosomes and hemidesmosomes) act to maintain the mechanical integrity of tissues by connecting the cytoskeleton to other cells or the extracellular matrix via linker proteins.

4. Anchoring junctions associated with the actin cytoskeleton (adherens junctions and actin-linked cell matrix adhesions) are involved in dynamic cell movements and cell signaling.

5. Occluding junctions prevent the passage of material between epithelial cells and maintain epithelial polarity.

6. Channel-forming junctions, are made up of transmembrane protein-protein interactions which produce pores (connexons) that allow low molecular weight substances to diffuse between cells.

7. Cell-cell adhesions mediated by cadherins as well as other transmembrane proteins such as the selectins and immunoglobulin superfamily members.

8. Integrins are primarily responsible for cell-matrix adhesion and integrin activity can be regulated.

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KEY WORDS:

anchoring junctions transcellular transport channel-forming junctionstight junctions connexon heterophilic zona occludens integrin N-CAMoccluding junctions plectin plaquesparacellular transport dystonin cell polarityadherens junctions talin adhesion beltdesmosome vinculin homophilichemidesmosome claudins selectinszonula adherens desmogleins connexinsfocal adhesion desmocollins epidermolysis bullosacadherin desmoplakin epitheliacatenins pemphigus gap junctionoccludins epithelial-mesenchmal

transition

Lecture Outline:

I. Cell Junctions

Types of cell junctions (Table 19-1A, Fig. 19-3)

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II. Anchoring Junctions

A. Function: to attach the cytoskeleton of one cell to that of another cell or to the

extracellular matrix anchoring junctions enable groups of cells to function as a unit (for

example, a sheet of epithelial cells)

B. Basic design (Fig. 19-4) actin or intermediate filaments bind to attachment proteins that are in

turn bound to transmembrane glycoproteins that adhere to similar transmembrane proteins on an adjacent cell or to components of the extracellular matrix

C. Four forms of anchoring junctions (Table 19-2):

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III. Cell-Cell Anchoring Junctions

A. Cadherins (Figs. 19-6,7,9a-c,10,12c) calcium-dependent, homophilic cell-cell adhesion molecules in the absence of calcium, there is a structural change and

cadherin is degraded transmembrane glycoproteins that bind homophilically to cadherins

on adjacent cells

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a complex superfamily of proteins with diverse expression patterns

cadherin-mediated homophilic adhesion enables disaggregated cells from amphibian cells to “sort out”

regulation of cadherin expression is important in developing tissues: epithelial-mesenchymal transition

B. Adherens Junctions (Figs. 19-14,15,16) enable cells in tissues to use actin cytoskeletons in a coordinated

way-mechanical integrity and morphogenesis in many epithelia, they are located near the apical surface, a.k.a.

adhesion belt or zonula adherens

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typically involve classical cadherins e.g. E-, N- P-, VE-. adherens junction cadherins are linked to the actin cytoskeleton by

catenins “purse string” contraction involved in morphogenetic movements

C. Desmosomes (Figs. 19-17a-d, 18) primarily act to provide mechanical integrity to tissues buttonlike plaques on lateral surfaces of epithelial cells typically involve non-classical cadherins, desmoglein or

desmocollin desmosomal cadherins connect to intermediate filament proteins

such as keratins (epithelia) or desmin (cardiomyocytes) via cytoskeletal linker proteins plakoglobin, plakophilin and desmoplakin

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D. Clinical correlation: pemphigus a blistering skin disease individuals with this disease produce antibodies against desmosome-

specific cadherins (desmogleins) in their skin desmosomes are disrupted pemphigus causes blisters because the skin cells (keratinocytes) are

not firmly attached to each other pemphigus is an example of an autoimmune disease

IV. Cell-Matrix Anchoring Junctions

A. Integrins (Fig. 19-45)

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transmembrane heterodimers, most of which act as cell-matrix adhesion molecules

at least 24 heterodimer combinations in humans binding to ECM requires calcium and magnesium

B. Actin-linked cell-matrix adhesion (Figs. 19-48b,49,51,52a) a.k.a. focal adhesions integrins connect the ECM to the actin cytoskeleton through linker

proteins talin and vinculin integrins can switch between active and inactive conformation-

important for cell motility this activity can be modulated by factors outside of the cell (outside-in)

or inside of the cell (inside-out)

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integrins can recruit intracellular signaling molecules to sites of cell-matrix adhesion

integrins control cell survival and proliferation in response to binding to ECM

integrins cluster to form strong adhesions

C. Hemidesmosomes (Fig. 19-46) hemisdesmosomes (half-desmosomes) attach the basal surface of

epithelial cells to the extracellular matrix (basal lamina) important for the mechanical integrity of many epithelia 64 integrin connects the ECM to the keratin intermediate filaments

through linker proteins plectin and dystonin the orientation of the interaction of the intermediate filaments with the

cytoskeletal linker protein differs from that in desmosomes – i.e., lateral in desmosomes and direct in hemidesmosomes

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D. Clinical correlation: Epidermolysis bullosa is a genetic disease in which the attachment of the basal cells of the epidermis to the basal lamina between the epidermis and dermis is disrupted. This results in blisters and very fragile skin. The attachment of the basal cells to the basal lamina occurs primarily via hemidesmosomes that attach the keratin intermediate filament cytoskeleton to the extracellular matrix via transmembrane proteins, integrins. There are several classes of the disease each related to a specific gene defect. Epidermolysis bullosa simplex is caused by mutations in keratin genes 5 and 19. Epidermolysis bullosa (junctional) is caused by mutations in laminin 5.

V. Occluding Junctions

A. Structure (Figs. 19-25,26) a.k.a. zona occludens or tight junctions (vertebrates) or septate

junctions (invertebrates) anchor epithelial cells to one another acting as selective barrier to

diffusion of molecules between cells and to proteins in plasma membrane

confer polarity to epithelial cells-apical and basolateral domains located near apical surface of epithelial cells

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an anastomosing network of strands in the plasma membrane that encircle the apical portion of epithelial cells

made up of transmembrane junctional proteins that bind each other and form the seal

barrier function increases as a function of the number of strands requires calcium claudins and occludins are major transmembrane proteins which link

to the actin cytoskeleton through ZO proteins

B. Function (Figs. 19-23,24,31) selective permeability barriers (paracellular transport)

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mediate transcellular transport e.g. intestinal epithelial cells by providing permeability barrier and segregating transport proteins

in combination with adherens junctions and basal lamina regulate cell polarity

VI. Channel-Forming Junctions

A. Structure (Figs. 19-34a,b,35) a.k.a. gap junctions separated by gap of 2-4nm usually located below adherens junction

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gap is spanned by proteins that form a channel (connexon) that selectively allows molecules less than ~1000 daltons to pass

connexins are proteins which make up connexons-6 connexins/connexon

~14 connexins encoded by separate genes, can form hetero- and homo-hexamers with different biochemical properties

B. Function (Figs. 19-33,37) allow selective passage of small molecules between cytoplasm of

neighboring cells; coupling cells electrically and metabolically permeability can be regulated

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C. Clinical correlation: Infertility The normal development of the ovarian follicle depends on gap junction-mediated communication between the oocyte and surrounding granulosa cells. The granulosa cells extend processes through the zona pellucida and make gap junctions mediated by connexin 37 (Cx37) which are important for the exchange of nutrients and signals involved in oocyte maturation. A mutation in the Cx37 gene in females can be one basis for infertility.

VII. Signal Relaying Junctions (Fig. 19-22c)

adherens junctions and actin-linked cell-matrix adhesions are involved in cell signaling events

synapses are specialized cell-cell junctions that are specialized for neurotransmission

Summary of cell junctions

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VIII. Other cell-cell adhesion molecules

A. Selectins (Fig. 19-19) transmembrane proteins that bind to carbohydrates on cell surfaces heterophilic, calcium-independent binding involved in leukocyte trafficking (weak adhesion and rolling)

B. Integrins (Fig. 19-50) L2 (LFA1 integrin) expressed on leukocytes and T-cells, involved in

strong adhesion and extravasation, interactions between T-cells and antigen-presenting cells

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C. Immunoglobulin superfamily (Fig. 19-20)

contain multiple immunoglobulin repeats, calcium independent mediate binding to integrins in vessel wall and on antigen-presenting

cells others mediate homophilic binding, such as neural-cell adhesion

molecule (N-CAM) N-CAM has many forms due to alternative splicing fine-tunes connections through weaker interactions than cadherins

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