55 terms

Basement Membrane

the basement membrane is not a
biological membrane (not a lipid bilayer)
basement membrane is made of
thin sheets of specialized ECM
basement membranes are found at the
basal surfaces of epithelial and endothelial cells
location of basement membranes
surround all muscle cells, fat cells, CNS and PNS
- filter
- cell adhesion site
- cell prolif and migration
- differentiation
- guides migrating cells during dev.
2 components of BM
- basal lamina
- reticular lamina
basal lamina
- deposited by epithelial cells
- made of laminin, fibronectin, type 4 collagen, HS, nidogen/entactin
reticular lamina
- deposited by CT fibroblasts
- type II collagen (reticular fibers)
ex of BM as a filter
- blood vessels
- intestinal epithelium
basement membrane in muscle
- connects adjacent cells and maintains integrity of tissue
- helps transmit forces generated by muscle cells
basement membrane in kidney glomerulus
- BM is twice as thick as in other tissues
- forms a filtrate in the urinary space for urine
4 components of basement membrane
- laminin
- type 4 collagen
- nidogen/entactin
- perlecan (HS proteoglycan)
laminin are what kind of proteins?
cell adhesion
what kind of chains do laminin make?
alpha beta and gamma
the integrin binding domains in laminins do not contain
RGD motif
laminin assemble into
trimers in the ER via coiled domains, and further stabilized by disulfide bonds
many laminins polyermize into a
network of filaments and layered sheets
the globular domains of laminins have
specific binding properties
the structure of laminins
- one alpha, one beta, and one gamma chain assemble to form trimers
- only the cross shaped trimers can self-polymerize into a network because interactions between alpha beta and gamma n-terminals domains are required
Type 4 collagen is composed of
trimers of chains
the sequence of type 4
dimers and tetramers of type 4 collagen can associate _____ or _____
laterally or end-to-end
type 4 collagen do not form
fibrils, they form flat sheet-like lattices
what does the type 4 collagen do for the basement membrane
the lattice provides a framework
- sulfated glycoproteins
- bind to both laminin and type 4 collagen
- bridge between laminin and type 4 collagen that forms networks in lung, heart, and skin
proteoglycans of basement membranes
- perlecan, aggrin, and collagen 18
- contribute much of the net negative charge of basement membranes due to their high sulfation
two other components of basement membranes
fibronectin and fibulin 1
how to cells adhere to BM?
via interactions between surface receptors and specific polypeptide sequences within BM proteins that serve as the receptor ligands. the main receptors are integrin and dystroglycan
intregin is a heterodimer of
alpha and beta subunits
the three parts of integrin
- extracellular matrix binding domain
- hydrophobic transmembrane domain
- short cytoplasmic tail for interactions with signaling molecules inside cell
integrin mainly binds to what in the basement membrane?
- collagen 4
- laminin
after integrins bind to BM, 5 steps:
1) signaling proteins bind to cytoplasmic tail of beta integrin
2) clustering of integrins
3) binding of adaptor and scaffolding proteins
4) assembly of actin
5) activation and autophosphorylation of FAK
how hemidesmosomes work
- intermediate filaments in basal keratinocyte attach to
- adapter plaque proteins (plectin, bullous pemphigoid 230 and 180) connect to
- alpha6beta4 integrin connects to
- laminin 5 connects to
- the rest of the basement membrane connects to
- anchoring fibrils (type 7 collagen)
dystroglycan are highly
dystroglycan receptors bind to
subunits of dystroglycan
transmembrane beta and extracellular alpha
dystroglycan helps organize ______ and ______
1) laminin polymerization
2) BM formation in muscle and epithelium
the DGC links
actin cytoskeleton and muscle fiber BM
laminin-DGC provides
stability to the muscle fiber plasma membrane under the force of contractions
3 steps of assembly of BMs
1) BM components are secreted by cell into the ECM
2) laminin LG domain binds to receptors on cell membrane and laminin LN domains interact with tripartite complex that promotes laminin polymerization
3) the other components (type 4 collagen) integrate with laminin network to assemble the BM
cells must travel through the basement membrane during three events
1) development
2) leukocyte trafficking
3) metastatic disease
proteases and other mechanisms dissolve BMs using 4 methods
1) invadopodia breaching
2) force breaching
3) BM disassembly through loss of receptors
4) cell egress
invadopodia breaching is used when?
in development and cancer metastasis
steps of invadopodia breaching
1) breaching cell initiates breach with invadopodia (plasma membrane protrusions)
2) this physically displaces the BM and directs invasions through a BM gap into the underlying cells
3) the BM gap expands through BM sliding over the underlying cells
5 steps of mechanical force breaching
1) as the growing embryo expands
2) becomes restricted laterally by uterine lining
3) embryo elongates in proximal-distal axis
4) BM breach is triggered by mechanical strain
5) cells exit through basement membrane gaps into visceral endoderm
BM disassembly through receptor loss happens due to
epithelial-mesenchymal transition during gastrulation
3 steps of BM disassembly through receptor loss
1) epithelial cells interact with underlying BM through dystroglycan
2) BM is lost under epithelial cells through loss of dystroglycan localization at cell-BM interface
3) invading cells de-epithelialize, ingress, and form into mesoderm and endoderm precursors
cell egress and ingress happens during
crossing of vascular endothelial BMs
8 steps of cell egress/ingress
1) leukocytes tranverse vessel wall during immune suriveillance by entering lymph
2) go through gaps in BM
3) exit through venules
4) at regions with reduced expression of BM components (LER) in capillary beds
5) tumor cells migrate away from primary tumor and intravasate via the blood
6) or by the lymphatic system
7) circulating tumor cells becomes lodged in capillary beds
8) activated endothelial cells may break down BM during vascular sprouting at the initiation of tumor angiogenesis
Epidermolysis bullosa (EB)/ JEB
- skin fragility
- nail dystrophy
- enamel hypoplasia (AI)
- hemidesmosomes don't form properly and blistering occurs
- results in severe scarring of skin in mouth and esophagus
- mutations in genes encoding components of basement membrane
- can be readily apparent in newborns after rigorous childbirth
amelogenesis imperfecta
- auto dom
- heterozygotes of JEB mutations (LAMB3)
- no skin defects
- enamel hypoplasia with deep linear groove and pits vertically
- possible mechanism: defective BM fails to fully de-repress enamel formation and ameloblast differentiation
- auto rec
- mutation of LAMA2 gene - encodes for laminin alpha2
- congenital hypotonia and joint contractures and progressive muscle weakness, non=ambulatory
- neural defects, including aberrant myelination of peripheral nerves
- difficulty chewing, gastro reflux, chest infections
merosin is also called
alport syndrome
- inflammation of renal glomeruli + deafness
- blood in the urine
- caused by mutations in COL4A3, COL4A4, COL4A5 coding for collagen 4 alpha chains
- usually on X-chromosomes so found frequently in males
Thin Basement Membrane Nephropathy (TBMN)
- benign familial hematuria
- glomerular BM is thinned, blood in urine
- no deafness and no progression to kidney disease
- caused by heterozygous mutations in COL4A3 or COL4A4 genes
- patients can be considered Alport "carriers"