15 - Epidermal and Dermal Adhesion Flashcards
Major cellular structures involved at cell-cell junctions in the epidermis
Desmosomes
Basement membrane adhesion complexes and related structures at the dermal-epidermal junction
Hemidesmosomes
Desmosome is also known as
Macula adherens
Major cell adhesion junction of the epidermis
Desmosomes
Anchor apposing keratinocyte cell surface membranes to the intercellular keratin intermediate filament network
Desmosome
Desmosomal cadherins
Desmogleins
Desmocollins
Plakins
Desmoplakin
Envoplakin
Periplakin
Armadillo family proteins
Plakoglobin
Plakophilins
Transmembrane proteins whose extracellular amino-terminal domains interact to form the trans-adhesive interface between cells, represented by the electron-dense midline of the desmoglea
Desmosomal cadherins
Contains the desmosomal cadherin cytoplasmic tails, with plakoglobin and the desmoplakin amino-terminal domain, and plakophilin
Outer dense plaque
Desmoplakin carboxyl-terminus interacts with keratin intermediate filaments, producing the
Inner dense plaque
Desmosomal cadherins mediate _____-dependent adhesion in a variety of epithelial tissues
Calcium
In humans, there are _____ desmoglein isoforms and _____ desmocollin isoforms
4
3
Expressed predominantly in the differentiated cells of the superficial epidermis
Dsg1
Dsg4
Dsc1
Expressed more strongly in the basal and/or suprabasal layers
Dsg2
Dsg3
Dsc2
Dsc3
Dsg: Largely limited to statified squamous epithelia in the skin
Dsg1
Dsg3
Dsg: Also strongly expressed in squamous cell carcinomas and other head and neck cancers, where it has been proposed as a potential molecular target for therapy
Dsg3
Dsg: Major desmoglein isofrom in most simple and transitional epithelia, as well as cardiac myocytes
Dsg2
Dsg: Prominent in desmosomes of the hair follicle, testis, and prostate
Dsg4
Dsc: Largely limited to skin and oral epithelia
Dsc1
Dsc: More widely expressed in most desmosome-containing epithelia and is the only desmocollin isoform in cardiac tissue
Dsc2
Dsc: Most strongly expressed in stratifies squamous epithelia of the skin and oropharynx
Dsc3
Desmosomal cadherins have been reported to engage in both homopholic and heterophilic interactions, although _____ interactions likely form the basis of epidermal intercellular adhesions
Heterophilic
Desmoglein 1 autoimmune target
PF
PV
IgA pemphigus (intraepidermal neutrophilic-type)
Desmoglein 1 genetic target
Striate PPK (AD)
Desmoglein 1 infectious target
SSSS
Bullous impetigo
Desmoglein 2 genetic target
ARVC (AD)
Desmoglein 3 autoimmune target
PV
PNP
IgA pemphigus (intraepidermal neutrophilic-type)
Desmoglein 4 autoimmune target
PF
PV
Desmoglein 4 genetic target
Hypotrichosis (AR)
Monilethrix (AR)
Desmocollin 1 autoimmune target
IgA pemphigus (subcorneal pustular dermatosis-type)
Desmocollin 2 genetic target
ARVC (AR and AD)
Desmocollin 3 autoimmune target
PV
Desmocollin 3 genetic target
Hypotrichosis (AR)
Desmoplakin I/II autoimmune target
PNP
Desmoplakin I/II genetic target
Striate PPK (AD)
Carvajal syndrome (AR)
Lethal acantholytic epidermolysis bullosa (AR)
Skin fragility-wooly hair syndrome (AR)
Plakoglobin genetic target
Naxos disease
Plakophilin 1 genetic target
Skin fragility and ectodermal dysplasia (AR)
Plakophilin 2 genetic target
ARVC (AD)
Corneodesmosin genetic target
Hypotrichosis simplex of the scalp (AD)
Diffuse PPK
Wooly hair
Left ventricular cardiomyopathy
Carvajal syndrome
PPK
Wooly hair
Nail dystrophy
Skin fragility-wooly hair syndrome
Diffuse PPK
Wooly hair
ARVC
Naxos disease
Desmoglein 1 is also targeted by hyperactive serine proteases in
Netherton syndrome
Plakoglobin is expressed
Throughout all layers of the epidermis and is ubiquitously expressed in all epithelia
Desmoglein _____ immunoreactivity is due to cross-reactivity with desmoglein
1 in pemphigus sera
4
No epidermal phenotype in affected patients
Dsg2
Dsc2
Directly bind to desmoplakin, and may also directly bind keratins and some desmosomal cadherins which is thought to aid in clustering and lateral stability of the desmosomal plaque
Plakophilins
Also known as gamma-catenin
Plakoglobin
Provides the major link between the keratin filaments and desmosomal plaque
Desmoplakin
Plakophilin _____ are both expressed throughout the epidermis, although plakophilin _____ is more predominant in basal compared to superficial epidermal keratinocytes
1 and 3
1
Plakophilin _____ is only expressed in the basal epidermal layer
2
Currently, there are no known human diseases associated with plakophilin
3
Envoplakin and periplakin are desmosomal plaque proteins expressed in the
Superficial layers of the epidermis
Envoplakin and periplakin autoantibodies are characteristic of _____ sera
Paraneoplastic pemphigus
Secreted glycoprotein that incorporates into corneodesmosomes and is also expressed in the inner root sheath of the hair follicle
Corneodesmosin
Ultrastructurally, basement membranes most offen appear as trilaminar structures, consisting of a central electron-dense region, known as the _____, adjacent on either side to an apparently less-dense area known as the _____
Lamina densa
Lamina lucida
The absence of distinguishable _____ in tumor biopsies is used as an indicator of malignancy
Basement membranes
The DEJ can be divided into _____ distinct zones
3
3 zones of the DEJ
- Keratin filament-hemidesmosome complex extending through the lamina lucida and lamina densa
- Lamina densa
- Sublamina densa
May result from shrinkage of the cell surface away from the lamina densa due to dehydration
Lamina lucida
The sublamina densa contains 2 readily distinguishable microfibrillar structures:
- Anchoring fibrils
2. Microfibrils
Account for 40-65% of the total protein of the basement mebrane
Collage
Ubiquitous components of basement membranes
Collagen IV Laminins Nidogens Heparan sulfate proteoglycans Fibulins
Collagen IV is a heterotrimer of 3 alpha chains. The _____ chains are ubiquitous.
Alpha 1 and 2
The 6 chains of collagen IV are distributed in 3 major networks:
- Alpha1-alpha2
- Alpha3-alpha4-alpha5
- Alpha1-alpha2-alpha5-alpha6
The chain compositions of collagen IV is determined by the
NC-1 domain
Collagen IV networks in the glomerular BM
Alpha1-alpha2
Alpha3-alpha4-alpha5
Collagen IV networks in the smooth muscle BM
Alpha1-alpha2
Alpha1-alpha2-alpha5-alpha6
Collagen IV networks in the DEJ
Alpha1-alpha2 (dominates)
Alpha1-alpha2-alpha5-alpha6g
Mutations in the genes encoding the alpha _____ chains cause pathologies in different organs, ranging from eye, brain, and muscle defect to small-vessel disease, which often underlies ischemic strokes and intracerebral hemorrhages and to the HANAC (hereditary angiopathy with nephropathy, aneurysms, and muscle cramps) syndrome
1 and 2
Structural aberrations in the genes encoding the alpha _____ chains cause different forms of Alport syndrome
3, 4, 5 and 6
Alport syndrome is a genetic disease characterized by
Nephritis
Deafness
The _____ chain is the antigen recognized by the circulating autoantibodies in the Goodpasture syndrome
Alpha3(IV)
Each laminin is a trimeric aggregate of _____ chain
1 alpha, beta and gamma
Major laminin of the epidermal BM
Laminin-5
Now called laminin 332
Mutations in the _____ laminin chains underlie junctional EB
Alpha3, beta3, gamma2
Mutations in the _____ laminin chain cause congenital muscular dystrophy
Alpha2
Relatively small molecules which bind laminins at a specific site within the gamma1 and the gamma3 chain, but also collagen IV, perlecan and fibulins
Nidogens 1 and 2
These three proteoglycans are characteristically present in vascular and epithelial basement membranes:
- Perlecan
- Agrin
- Collagen XVIII
Lack of _____ caused basement membrane deterioration in regions under increased mechanicsl stress, manifesting as lethal cardiac abnormalities and skin blistering
Perlecan
Major heparan sulfata proteoglycan of neuromuscular junctions and renal tubular basement membranes
Agrin
Considered to be a hybrid collagen-proteoglycan in various organs
Collagen XVIII
Transmembrane heparan sulfate proteoglycans present on most cell types, including basal keratinocytes of the epidermis
Syndecans
Family of highly conserved, calcium-binding extracellular matrix proteins
Believed to function as intermolecular bridges that stabilize supramolecular organization of extracellular matrix molecules, such as elastic fibers and basement membranes
Fibulins
Genetic defects of the genes encoding fibulin 4 and 5 cause different forms of
Cutis laxa
The 230-kDa bullous pemphigoid antigen 1, or BP230 is a protein with homology to _____, which bind intermediate filaments
Plakins
Major component of the hemidesmosomal inner dense plaque
BP230
Ablation of BP230 is associated with
Epidermolysis bullosa simplex
Major antigen in bullous pemphigoid
180-kDa bullous pemphigoid antigen 2 or BP180
180-kDa bullous pemphigoid antigen 2 or BP180 is a transmembrane collagen known as
Collagen XVII
Mutations in collagen XVII cause
Junctional epidermolysis bullosa
Plectin, another _____ homolog, is also a component of the hemidesmosome
Plakin
Mutations of _____ result in epidermolysis bullosa simplex with progressive muscular dystrophy and, in some cases, epidermolysis bullosa with pyloric atresia
Plectin
One key component of the hemidesmosome is the _____. It has a high affinity for laminin 332 and is essential to integration of the hemidesmosome with the underlying basement membrane
Integrin alpha6beta4
Mutations in either alpha6 or beta4 chains result in
Junctional epidermolysis bullosa associated with pyloric atresia
A member of the widely expressed cell surface transmembrane proteins of the tetraspanin family, _____, is also a component of the hemidesmosome. It forms complexes with alpha3beta1 and alpha6beta4 integrins at the basolateral surface of basal keratinocytes and stabilizes their functions
CD151
In addition to the expression of _____ in several tissues like the kidney and the skin, its gene also encodes the MER2 blood group antigen on erythrocytes
CD151
_____-negative patients presented with hereditary nephritis, sensorineural deafmess, pretibial epidermolysis bullosa, and beta-thalassemia minor
MER2
In addition to the hemidesmosomal components, other adhesion molecules are known to be present at the basolateral aspect of basal keratinocytes, for example, _____, the receptor for the laminin 332-311 complex in the basement membrane between the hemidesmosomes, and another transmembrae collagen, type _____
Integrin alpha3beta1
XIII
Mutations in the _____ gene cause a rare systemic disorder with interstitial lung disease, nephrotic syndrome, and epidemolysis bullosa
Integrin alpha3
Disorder with skin blistering in infancy, progressive poikiloderma, sun sensitivity, and skin cancer
Kindler syndrome
Mutation in Kindler syndrome
Kindlin-1
The anchoring filaments contain _____ and the ectodomain of _____, 2 ligands that interact with each other
Laminin 332
Collagen XVII
The major alpha3-containing laminin in the lamina densa between hemidesmosomes is probably the
Laminin 332-311 complex
The N-termini of laminin 322 bind to _____, the main component of the anchoring fibrils in the sublamina densa that, in turn, binds tightly to ______ containing fibrils so that anchoring filaments and fibrils are connected to each other and to the dermis
Collagen VII
Collagen I
Major component of the anchoring fibrils
Collagen VII
The collagen _____ molecule is distinguished from other collagens in that it has a very long triple-helical domain, 450 nm in length
VII
Anchoring fibrils are further stabilized by tissue _____, which catalyzes the formation of covalent crosslinks
Transglutaminase
In the acquires form of epidermolysis bullosa, epidermolysis bullosa aquisita, and in bullous systemic lupus erythematosus, autoantibodies target mainly the
NC-1 domain of collagen VII
Mutations in _____, the gene encoding _____, result in dystrophic epidermolysis bullosa
COL7A1
Collagen VII
Collagen, a family of 28 different collagen types, are the most abundant proteins in the dermis and represent _____% of its dry weight and _____% of its volume
75
20-30
All collagens have a basic structure of
3 alpha-chains, which have glycine as every third amino acid
In the dermis, the classic, cross-branded fibrils recognizable in the electron microscope contain collagen
I, III, V, XII, and XIV
In contrast, collagen _____ polymerizes into microfibrils
VI
Other collagens are needed to provide cohesion of the epidermis or the vascular structures with the dermal extracellular matrix, for example, collagens _____ in the epidermal basement membrane or collagens _____ in the vascular basement membrane zone
VII, XIII, XVII, XXIII
VIII, XV, XVIII
Provides dermal elasticity
Elastin
Elastin molecules are rich in repetitive (hydrophilic/hydrophobic) sequences and are highly crosslinked
Hydrophobic
Elastic fibers can be stretched by _____% or more, and still return to their original form
100
Main componenrs of elastic fibers
Elastin (90%)
Microfibrils
Negativelg charged polysaccharides that can bind large amounts of ions and water
Glycosaminoglycans
Four different proteoglycan-bound glycosaminoglycans are known
- Chondroitin sulfate
- Dermatan sulfate
- Keratan sulfate
- Heparan sulfate
Major proteoglycan in the dermis
Associated with elastic fibers and forms huge complexes with hyaluronic acid, which provides the skin with its tautness
Versican
Ubiquitous glycosaminoglycan without protein core, a giant polysaccharide composed of N-acetylglucosamine/glucuronic acid disaccharides
Hyaluronic acid
Majro heparan sulfate proteoglycan of basement membranes that can sequester and present growth factors to their receptors
Perlecan
Hybrid collagen/proteoglycan found in epidermal and vascular basement membranes in the skin
Collagen XVIII
Small leucine-rich proteoglycans
Multiple functions:
-Bind to collagen fibrils and regulate their assembly
-Bind TGF-beta
-Connected to immune reactions by signalling through toll-like receptors
Decorin
Biglycan
Transmembrane and glypicans membrane-anchored heparan sulfate proteoglycans
Control cell adhesion to the matrix and interact with multiple extracellular proteins, including growth factors, and thereby regulate cell functions
Syndecans
