Cell Adhesion Flashcards
Ig-CAMs
first, to rec self, Igs developed from Ig-CAMS to recognize other transient and dynamic neural and lymphocyte interactions - mediates specific interactions between lymphocytes and neural homophilic (N-cam + N-cam) and heterophilic (N-Cam binds to integrin, binds to ECM) Calcium independent Subverted as viral receptors - viruses can bind and enter cells - unregulated after virally induced damage! increase effect
proteoglycans
bind cells to ECM calcium independent glycerin side chains - bind growth factors, sequester and weather cell adhesion + signal, linker proteins, like cartilage, CD44 - expressed in cancer cells
Selectins
Calcium dependent! for strcture bind to sugars via a lectin domain sugars - encode greater repertoire of specificity than proteins lymphocytes patrolling endothelial lining of blood vessels - rec special sugars on the endothelial proteins (vascular addressins), used to roll along (need integrings for extravasation) weak adhesion and rolling!
Integrins
heterodimer - alpha and beta subunits! bind divalet cations (ca2+) and induce conf change in adhesive interface - adhesion bind to many ECM proteins of basal lamina (collagen, fibronectin, laminin) conformational change –> activate ectodomain –> cluster ingegrins in adhesive patches (hemidesmosomes, focal contacts) at these sites –> bind cytoskeleton through adaptor proteins bound to cytoplasmic domain
connect ECM to the cytoskeleton at focal contacts and hemidesmosomes
potentiate growth and survival signals! GF –> stim cell to proliferate –> with augment pway only if integrins are engaged (cells have to be in contact w the matrix for cell survival)
Cadherins
bind Ca 2+ and mediate cell-cell adhesion
at desmosomes and adherens junctions
highly conserved! 5 extracellular repeats of 110 AA - each ectodoman has negatively charged AA - bind Ca2+ ions –> conf change –> rigidifies –> adhesion/protect from proteolysis
each ectodomain folds into beta barrel (like Ig-CAMs)
homophilic and specific
loss associated w cancer
initiate cell contact w cadherins on tips of filopodia
puncta adherens
caderens used to initiate cell contact
on filopodial tips
zonula adherens
cardiac discs, belts in polarized epithelia
in polarized cell - arrange in belt, just below apical surface, harness actin filaments ot plasma membrane
initiate cell adhesion and transducing changes in cell and tissue shape!
initate cell adhesion
catenins
promote clustering of cell-cell adherins junctions
velcro! like zipper
alpha - bound to actin
beta - bound do E-cadherin
structure of adherens junction
velcro - caderens not sticky by themselves!
p120
part of adherens junction
prevents cadherin endocytosis and regulates actin remodeling
not statically on cell surface
plankglobin/beta-catenin
links between cadherins and alpha catenin
binds to cadherins via positively charged groove - bridge between alpha catenin and E-cadherin - if phosphorylated, ca’t bind! can regulate adhesion post-translationally
alpha-catenin
regulate local actin assembly and organization at sites of cell-cell adhesion
teminal bar complex
- tight junction
- zonula adherens
- desmosome
zonula adherens and desmosome - widened intracellular space with filament
E-cadherin
associated with stable differentiated epithelial tissue- if lose it, invasive, migratory, rapid proliferation
N-cadherin gain associated with tumor metastisis and invasion
adherens and cancer
E-cadherin loss
N-cadherin gain
alpha catenin loss
Wnt signaling
Wnt - function of catenins outside of cell junctions, wnt –> allows beta catenin to accumulate outside of cell adhesion
if no wnt –> beta catenin would not be outside of cell adhesion because it would be drgraded by APC
Wnt - inactivates cytoplasmic complex of APC that targets cytosolic beta-catenin for degredation - no beta catenin degredation!
beta-catenin can enter nucleus and regulate growth genes
colon cancer = mutation in APC (APC destroys beta-catenin if not in the cell junction)
APC facilitates beta-catenin degredation - increase in beta-catenin in colon cancer –> not degraded –> activates genes!
Desmosomes
symmetrical circular membrane specializations
REINFORCE cell adhesin
bind intermediate filaments (keratin) - form resilient supracellular web, 10 nm intermediate filaments
found in all epithelia but most in stressed epithelia and heart (intercalated discs)
wider, dense, parallel plaques - 20-30 nm
midlines
buttons and suspenders
Desmosome structure
plakoglobin
plakophilin
desmosomal catenins
desmosomal cadherens bind directly
intermediate filament cytoskeleton linkers
highly conserved and identical in all tissues
desmoglians
desmocollins
cadherins in desmosomes
ectodomains are similar but cytoplasmic domains are different
Pepmhigus vulgaris
autoimmune
desmoglian 3
cadherin affected by pemphigus vulgaris - antibodies attack dsg3 - skin and oral cavity
deep blisters above basal cells and mucus membrane
pemphigus foliaceus
dsg1
autoimmune
desmoglian, cadherin attacked
target of pemphigus foliaceus autoantibodies, Staph A. and Bollous Impetigo toxins
superficial blisers
toxins cleave Dsg1 - crustier higher level
desmoplakin
connect to intermediate filaments! like alpha-catenin?
Difference between desmosomes and adherens junctions
Naxos Disease
mutation in C-terminal of plakoglobins
wooly hair, heart problems, crusty hands, early death
plagoglobin fails to localize at intercellular junctions
Carvajal Syndrome
autosomal recessive mutation in desmoplakin (C-terminal truncation)
connects desmosomes to intermediate filaments
haploinsufficiency
heart defects
no desmoplakin or plakoglobin linked to intercalated discs
arhythmogenic cardiomyopathy
mutations in genes encoding desmosomal proteins
desmocollins, desmoglein, desmoplakin, plakoglobin, plakophillin
cells don’t beat together - need cell adhesion sites
not protected from sheer stress by mechanical junctions (adherens junctions and desmsomes) at intercalated discs
staphylococcal scalded skin
bullous impetigo
Dsg1 - bacterial toxins attack
ectodermal dysplasia
plakophilin
genetic
size of filaments
actin - 5 nm
intermediate - 10 nm (highly stable!)
microtubules - 25 nm
Intermediate filaments
major proteins (10-85% of total proteins)
mechancal integrators that resist stress and provide structural integrity
large family
differentially expressed to serve specific cytoarchitectural needs
specific needs per cell
supracellular web - in tissue, through connections to desmisomes/hemidesmosomes
Intermediate filament rod
central rod - 310 AA
4 highly conserved alpha helical domains
3 not conserved non-alpha helical domains
head and tail: varying, non helical
intermediate filament dimer
first and fourth residues are hydrophobic! these residues align when 2 rods coil together to make a greasy seal
parallel - heads together, tails together
1 acidic, 1 basic (some homopolymeric)
2 dimers associate antiparallel and staggered
Intermediate filament structure
dimers - antiparallel to make tetramers
tetramers elongate linearly to make protofilaments
two protofilaments stact to form protofibril
4 protofibrils twine around each other to for filament
32 polypeptides!
mutations in intermediate filaments
mutations at conserved ends of rods - cause keratin clumping!
mutations in L1-2 - affect packing! weaker!
Structure of Skin
EPIDERMIS: prevent water loss and infection
Stratum Corneum (dead)
Granular layer
Spinus layers - terminally differentiated in skin, make keratins, ross link, make h2o resistent barrier, die
basal layer - tall cells - high nucleus to cytoplasm ration - proliferation
basal lamina
DERMIS
EBS
epidermal blistering just above basal lamina
aggravated by trauma and heat
3 subtypes: Dowling Meara, Weber Cockayne, Koebner
absence or weakening of filament network
keratin aggregates
intraepidermal cytolysis
within basal epidermal cells - gap in tall mitotically active cells - lack of filament in that layer OR lots of keratin (severe), weak filaments (mild)
K5/K14
genes for keratins in basal cells of all stratified epithelia
Keratins - obligate heterodimers of one acidic and one basic keratin polypeptide
Dominant: abnormal protein produced which disrupts large molecular complex, if mutation in K5-K14 still needs it
Recessive: insufficient functional protein produced
Dowling-Meara
most severe EBS
filaments clump! no long filaments
mutations at the ENDS of rods
Weber Cockayne EBS
Mutations at central non helical (L1-2 Region) - and at very beginning of rod, mild - thin!
Koebner EBS
most mold - mutations in helical/intron regions? thin filaments
K1/K10
keratin in epidermal suprabasal layer, first express K5/K14 then change to K1/K10
mutations –> EH
EH
flacid blisters, thick keratotic plaques
AD - mutations in genes encoding K1/K10 keratins in suprabasal epidermal cells
same hotspots at the end of the rods on K1/K10
mosaic EH - post zygotal mutation
mutation is higher - still have mitotically active layer, proliferation to overcompensate
JEB
hemidesmosomes! blister at basal lamina region
hemidesmosomal adhesion to basal lamina
present at birth, some mortality
large blisters between epidermis and dermis
autosomal receessive - many different types due to proteins involved in cell-matrix adhesion
failure to thrive and iron deficiency
hemidesmosomes
keratin - K5/K14
intracellular plaque - Plectin, BPAG1
transmembrane proteins (integrin a5b4, BPAG2)
anchoring filaments - Laminin V
Lamina densa - Collagen IV, Laminin
JEB + muscular dystrophy
mutation in plectin
GABEB
BPAG-2 mutation (transmembrane protein)
rare
JEB + pyloric atresia
a6b4 integrin - projectile vomiting
Classical JEB
laminin V - anchoring filaments mutation
DEB
in dermis! mutationin Collagen VII anchoring fibrils
no anchoring fibrils
lots of scarring
AR and AD - all due to Collagen VII mutations - the major component of anchoring fibrils
increased risk for squamous cell carcinoa
infection
Collagen VII
forms anchoring fibrils, stich dermis to epidermis by binding to laminins and collagen IV in basal lamina and anchoring plaques
collagedns are connected to lamins - triple helix and non collagenous head and tail
2 tails line up and cleaved off - bundle - 6 polypeptides - 3 heads on one side, 3 on the other
immunoflourescence against Collagen IV in basement membrane. Where are blisters for DEB and EBS?
membrane on roof/floor of BLISTER
DEB - collagen IV on blister roof
EBS - collagen IV on blister floor
antibody panel for BPAG1/2. where is it on blister?
EBS - base
JEB - roof
DEB - roof
antibody panel for Laminin 1. Where on blister?
EBS - base
JEB - base
DEB - roof
antibody for Collagen IV. where on blister?
EBS - base
JEB - base
DBS - roof
Bullous Pemphigoid
autoabs bound to bpag 1, blisters between epidermis and dermis
Cicatricial Pemphigoid
autoantibodies to Laminin V
blisters between empidermis and dermis
eye
Disorders of Spinous layer
GENETIC:
EPPK (K9)
EH (K1/K10)
AUTOIMMUNE:
Pemphigus foliaceus (DSG1)
Disorders of basal layer
GENETIC:
EBS - K5/K14
AUTOIMMUNE:
Pemphigus vulgaris (Dsg 3)
Disorders of Basal Layer/Lamina interface
GENETIC:
JEB: a6B4, BPA2
AUTOIMMUNE:
Bullous Pemphigoid (BPAG2, BPAG1)
Disorders of Dermis
GENETIC:
DEB (Coll VII)
AUTOIMMUNE:
EB Acquisita (Col VII)
hemidesmosomes/EB structure
