ECM and integrin receptors Flashcards
Describe the ECM and its roles.
- complex meshwork of extracellular molecules
- secreted and assembled by local cells (fibroblasts)
- provides supportive framework to hold cells and tissues together
- found in multicellular organisms only
- critical for development of distinct tissues and organs
- regulates many cellular processes through interaction with integrins
Describe integrin receptors and their roles
- they are the principle matrix receptor in animal cells
- membrane-spanning receptors that provide a link between the inside of the cell and the ECM
- bind to ECM proteins to activate intracellular signaling pathways
- transduce cells bidirectionally across the membrane (inside out and outside in)
- only in multicellular organisms
- regulates many cellular behaviors
Describe the role of ECM and integrins in cancer.
Changes in ECM and integrin expression are associated with many pathological conditions, including cancer.
- ECM serves as barrier to tumor progression (basal lamina)
- alterations in ECM (tension) can contribute to tumor progression
- ECM and integrins can be exploited to target tumors therapeutically
Which transmembrane adhesion protein is responsible for transducing the activating signal to focal contact-associated kinase (FAK)?
integrin
What are the components of the ECM?
- GAGs: unbranched polysaccharide chains composed of repeating disaccharide units usually attached to a core protein. When attached to the protein it is called a proteoglycan
- fibrous proteins: collagen, elastic fibers, fibronectin
What are the four types of GAGs?
- hylauronan (simplest GAG)
- heparan sulfate
- chondroitin/dermatan sulfate (important in joints)
- keratin sulfate
How do different types of GAGs differ?
differ based on types of sugars, linkage between sugars, and sulfation of sugars
Describe complex GAGs.
they are sulfated to add a negative charge, thus attracting sodium ions and H2O to keep the ECM well hydrated and at a large volume. One example of this type of GAG is heparan sulfate.
Describe the proteoglycan core protein.
- core protein binds GAG molecules. One bound is a decorin
- many bound is an aggrecan
- core proteins are glycosylated and secreted through ER-golgi-mediated secretory pathway
What are the benefits of the large size of GAGs?
Because the size is due to hydration and sweeling, they enable the matrix to withstand compressive forces while allowing rapid diffusion of nutrients (not too dense) between blood and tissue cells. Hyaluronan allows tissues to resist compression and are found in ECM of load-bearing joints.
What are the functions of proteoglycans and GAGs?
- selective sieve to regulate molecular trafficking
- regulation of chemical signaling (e.g. heparan sulfate can bind and bring FGF to FGFR)
- regulation of other secreted proteins
- act as co-receptors
What are some examples of GAGs and proteoglycans regulating other secreted proteins?
heparan sulfate can immobilize and sequester chemokines together for an immune cell;
=dermatan sulfate can organize collagen;
- others can sterically block protein activity;
- others can protect proteins from proteases
How do proteoglycans and GAGs act as co-receptors?
- some proteoglycans are tethered to the plasma membrane of cells, and therefore aid in the activation of cellular receptors
- syndecans: heparan sulfate present FGF to FGFR
- betaglycans: present TGF-beta to TGF-beta receptor
What is Hurler’s syndrome?
- autosomal recessive
- accumulation of heparan sulfate and dermatan sulfate as a result in deficiency in the enzyme which degrades them
- cells cannot grow normally because ECM is overgrown
- causes dwarfism, mental retardation
Role of collagen in ECM?
provides tensile strength to matrix. Found in all multicellular organisms.
Describe the structure of collagen.
- 3 alpha helices wrapped around each other
- glycine allows for close interaction of 3 helices
- proline rings stabilize the helices
- hydroxyproline, hydroxylysine residues also stabilize the triple helix
Describe the steps of fibrillar collagen formation.
- pro-alpha chain is made in the ER/golgi
- selected prolines and lysines are hydroxylated
- selected hydroxylysines are glycosylated
- three pro-alpha chains are self-assembled
- procollagen triple helix is formed and leaves golgi in secretory vesicle
- procollagen is secreted from the cell
- propeptides are cleaved (N and C termini) to prevent collagen aggregation
- collagen molecules self-assemble into fibrils, directed by crosslinking of lysine residues
- collagen fibrils aggregate to form a collagen fiber
What are the different patterns of collagen organization?
- wickerwork pattern: collagen fibers are oriented perpendicularly to each other (e.g. skin)
- bundled pattern: collagen fibers are oriented parallel to each other (e.g. tendon). these are the stronger type
Describe fibril-associated collagens.
- type IX (cornea) and type XII (tendon) collagens
- triple helix structure is interrupted with nonhelical segments to allow for bending
- retains propeptides after secretion and don’t form fibrils
- bind to surface of fibrillar collagens and to other ECM components to determine organization of collagen matrix
How is the ECM able to recoil after transient stretch?
Elastic fibers allow for recoiling. They can recoil after stretching 1.5 times their length. This is very important in skin, blood vessels, and lungs. The network of elastic fibers interwoven with nonelastic collagen fibrils regul\ates the elasticity of tissues.
What are elastic fibers composed of?
- elastin is primary component
- rich in lysine and proline (some hydroxyproline)
- tropoelastin molecules are secreted from cell where they assemble in association with plasma membrane and generate fibers from lysine crosslinking
- random coiled assembly allows stretching and retratction (hydrophobic regions for elasticity, and alpha helices for crosslinking)
- deficiency leads to artery narrowing
What is fibronectin?
- large glycoprotein important in cell-ECM interactions
- consists of a dimer with 2 large polypeptide chains joined by disulfide bond at the C termini
- each subunit contains 5-6 functionally distinc domains for binding to a specific molecule or cell (e.g. cell-binding domain, collagen-binding domain, heparan-binding domain)
What mediates fibronectin binding to integrin?
The type III FN repeat contains an RGD residue sequence which binds to integrins. Synergy sequences at this domain can also bind integrin.
How is fibronectin fibril formation mediated?
fibronectin normally travels throughout the blood, and only forms fibrils on surface of cells, which requires integrins:
- fibronectin dimers bind integrins
- linkage to intracellular cytoskeleton causes tension which pulls fibronectin into an open conformation, revealing cryptic binding sites
- fibrils can then self-assemble
Describe laminin.
- primary component of basal lamina
- heterotrimeric protein assembled in shape of assymetric cross. (three heads + tail region)
- combinations of chain types can yield different types of laminins
- contain binding sites for other laminins and integrins to make a laminin network
- loss of laminin-gamma-1 is embryonic lethal
How is basal lamina assembled?
- components are secreted from cells
- tails anchored by matrix receptors, allowing heads to interact
- laminin coordinates assembly of laminin and collagen networks by nidogen and perlecan linkers
