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Lecture 12 and 13
School of Medical Sciences
The University of New South Wales Dr Mark Hill Cell Biology Laboratory Room G20 Wallace Wurth Building Email: m.h...)
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ANAT3231 - Cell Biology
Lecture 12 and 13
School of Medical Sciences
The University of New South Wales
Dr Mark Hill
Cell Biology Laboratory
Room G20 Wallace Wurth Building
Email: m.hill@unsw.edu.au
UNSW Copyright Notice
ExtraCellular Matrix (ECM)
Cell-Cell, Cell-Matrix Adhesions
ECM References
Essential Cell Biology
Ch19 p594-604
Molecular Biology of  the Cell
Animal and Plant ECM
Material secreted and deposited by cells
ANAT3231 Lecture 8
Extracellular matrix
ECM Function
Support for cells
Pattern of ECM regulates
cell division
Growth factors
ECM Structure- Glycoproteins
Collagen- main fibers
Hydrated Matrix
high carbohydrate
Shapes and Sizes ECM molecules
tensile strength and elasticity
half total body proteins (by weight)
Collagen Components
Insoluble glycoprotein
protein + carbohydrate
high glycine and 2 modified amino acids
Collagen Structure
Collagen Protein
3 polypeptide (a) chains
left hand helix, forms fibers
14 different (vertebrate) collagens by different combinations of  a-chains
numbered I - XIV
Type I, II, III
main fibers, flexible
Type I
bone, skin, tendons
90% of all collagen
Type II
Collagen Fibers
Type I, II, III cross striated
showing overlapping packing of individual collagen molecules
Type IV fine unstriated
sheet-like supportive meshwork
mature basal laminae
tracks for embryonic migration
barriers for cell migration
Type V-XII
smaller diameter fibers than I-III
no striations
Collagen Fibers
Collagen Non-striated
Collagen Synthesis
Endoplasmic Reticulum
mRNA attached to ER
protein synthesized into ER lumen
3 proto-a-chains form soluble procollagen
moved to golgi apparatus
Golgi Apparatus
packed into secretion vesicles
fuse with membrane
Outside Cell
procollagen processed by enzymes outside cell
assemble into collagen fibers
Collagen Biosynthesis
Collagen Diseases - Excess
excess collagen
lung- pulmonary fibrosis
overproduction of collagen I
liver- over consumption of alcohol
arteries- atherosclerosis
Collagen Diseases - Insufficient
insufficient collagen
Ehlers-Danlos syndrome
skin and tendons easily stretched
contortionists often suffer from this disease
Osteogenesis imperfecta
brittle-bone syndrome
mutation in Type I procollagen
fail to assemble triple helix
degrade imperfect collagen
Leads to fragile bones
Collagen Diseases
dietary Vitamin C deficiency
needed for hydroxylation
Proline  ->  Hydroxyproline
form too few hydrogen bonds in collagen
skin, bone, teeth weakness and malformation
blood vessels weakened, bleeding
Glycosaminoglycans (Gags)
10% by weight but fill most of space
unbranched polysaccharide chains
disaccharide subunits
amino sugar
4 groups
chondroitin sulphate, dermatan sulphate
heparan sulphate, heparin
keratan sulphate
Glycosaminoglycans- Hyaluronan
Also called hyluronic acid or hyaluronate
produce a “cell-free” space
for cell proliferation and migration into
heart, cornea
in areas of compression
tissues, joints
Hyaluronan Synthesis
synthesized at plasma membranes
nascent chains directly extruded into ECM
Proteoglycans- Function
trap water
resistant to compression
return to original shape
occupy space
link to collagen fibers
form network
in bone combined with calcium hydroxyapatite, calcium carbonate
Cell adhesion
embryonic migration
Proteoglycan- Disease
Cancer development
altered types and kinds of proteoglycans formed by cells
normal cells -> malignant
Cartilage breakdown
chondrocytes elicit a catabolic response which exceeds anabolism of new matrix molecules
Degrade proteoglycan (aggrecan)
Also a mouse model generates antibodies to proteogycan
Cell Adhesion to ECM
Direct linkage to collagen or proteoglycan
insertion of fibers into membrane
covalent attachment to membrane lipid
Linking glycoproteins
Fibronectin Structure
Fibronectin Structure
dimer connected at C-terminal
S-S linkages
rigid and flexible domains
cell binding segment RGDS
binds receptor in membrane
domains bind
heparin sulphate
hyaluronic acid
Fibronectin Function
cell adhesion
migration pathways
blocking fibronectin with antibody
prevents neural crest migration
extension of axons and dendrites
basal laminae
under skin and between organs
clotting process, link to fibrin
Laminin Structure
Laminin Structure
cross-shaped glycoprotein
3 polypeptides a, b1, b2
carbohydrate (13% by weight)
Mr 900K
separate binding domains
collagen IV
heparin sulphate
cell binding
cell specific binding
liver, nerve
cell surface receptor
Laminin Function
cell adhesion
migration pathways
stimulates growth of axons
development and regeneration
basal laminae
most abundant linking glycoprotein
Integrin- Structure
Integrin Function
cell membrane receptor for ECM linkers
binds RGDS motif
2 subunits alpha (α) and beta (β)
linked to cell cytoskeleton actin microfilaments
via talin and vinculin
focal contacts
For Review see
Integrin signaling revisited. Schwartz MA.Trends Cell Biol 2001 Dec;11(12):466-70
Focal Adhesions- Microfilaments
Cell signalling
Modify cell cytoskeleton
Activate intracellular signalling pathways
Cell motility
Integrin- Function
Activate members of  Rho-family of small GTPases
Conversely, Rho- and Ras-family proteins can influence the ability of integrins to bind their ligands
control of cell motility, and therefore on invasive and metastatic behavior
Integrin binding ECM has effects on cell survival, particularly for cells of epithelial origin
specific integrins have selective effects on efficiency of signal transduction in cell survival pathways
Text modified from: New aspects of integrin signaling in cancer. Semin Cancer Biol 2000 Dec;10(6):407-14
Integrin Signaling
Adhesive Signalling
Integrin and Laminin
Several integrin heterodimers act as laminin receptors on a variety of cell types
alpha 1 beta 1
alpha 2 beta 1
alpha 3 beta 1
alpha 6 beta 1
alpha 7 beta 1
alpha 6 beta 4
Microsc Res Tech 2000 Nov 1;51(3):280-301
Integrin and Laminin
Roles of laminin-binding integrins in adhesion-mediated events in vertebrates
embryonic development, cell migration and tumor cell invasiveness, cell proliferation, differentiation and basement membrane assembly
essential role for receptors in maintaining cell polarity and tissue architecture
Text from: Microsc Res Tech 2000 Nov 1;51(3):280-301
Basal Lamina Experiment 1
Basal Lamina Experiment 2
Neuromuscular junction
Basal lamina directs acetylcholinesterase (AChE) accumulation at synaptic sites in regenerating muscle
skeletal muscle damaged such that basal lamina sheaths of the muscle fibers spared
new myofibers develop within sheaths and neuromuscular junctions form at original synaptic sites
regenerated neuromuscular junctions have junctional folds and accumulations of acetylcholine receptors and AChE
Anglister L, McMahan UJJ Cell Biol 1985 Sep;101(3):735-43
Adhesion Junctions
Adherens (cell-cell)
cadherin (E-cadherin) Links to cadherin in neighboring cell
Adherens (cell-matrix)
Integrin Links to extracellular matrix
ECM Scaffold- Tissue Engineering
“Decellularized tissues and organs have been successfully used in a variety of tissue engineering/regenerative medicine applications, …Each of these treatments affect the biochemical composition, tissue ultrastructure, and mechanical behavior of the remaining extracellular matrix (ECM) scaffold, which in turn, affect the host response to the material.”
Decellularization of tissues and organs. Biomaterials. 2006 Jul;27(19):3675-83. Epub 2006 Mar 7.

Latest revision as of 20:14, 26 April 2009