ECM and Cell-Matrix interface Flashcards
Describe ECM.
a gel-like ground substance, non cellular component within all tissues and organs, consisting of:
- fibrous proteins
- non-fibrous glycoproteins
- proteoglycans
- water
What is a significant characteristic of ECM?
provides a physical scaffolding that initiates biomechanical and biochemical signals required for cellular adhesion, cell division, migration, tissue remodeling, and repair and tissue development.
The ECM is composed of mostly what kind of collagen?
type 1
What are all the functions of ECM?
- physical fxn: support tissues to maintain shape and flexibility
- biochemical fxn: controls cell growth, differentiation, tissue. remodeling, repair. inflammation, and deposition of fat.
- regulatory fxn: binding, integrating and controlling the presentation of growth factors and other igands to the receptor of the cells and initates signaling.
- Homeostatic fxn: balance between matrix deposition and its degradation by MMPs
- Specificity fxn: diversity and specificity of ECM composition and organization lend itself to solid structures found in bones and teeth or to a flexible structures found in cartilage and tendons.
- Loss of function: disruption to ECM network will result in loss of cell and tissue homeostasis and lead to diseases like cancer
What are the generalizations of ECM proteins?
ECM proteins are secreted proteins. There are two different kinds of proteins: fiber forming and non-fiber forming
What are examples of fiber-forming proteins? What is the function of fiber forming proteins?
collagen and elastins; providng structure and adhesive functions
What is an example of non-fiber forming proteins?
Laminin and fibronectin
What is fibronectin?
a glycoprotein presented as a dimer in plasma and dimer or multimeric form in ECM
- 230-270 kDa with 20 different isoforms
What is the function of fibronecin?
- Binds cell surfaces and various compounds such as: collagen, fibrin, heparin, and actin
- regulates cell adhesion, cell motility, wound healing, maintenance of cell shape, blood coagulation, host defense and metastasis
What is RGD tripeptide sequence?
a Arg-Gly-Asp sequence in fibronectin that is essential for collagen type 1 deposition which results in osteoblast and odontoblast mineralization.
How does the ECM link to the cell?
By the integrin-fibronectin collagen complex.
The integrin dimer is embedded in the cell membrane and is ready to bind to fibronectin . The fibronectin has the RGD code to bind to collagen.
What is laminin?
a major non-collagenous glycoprotein; a heterotrimer of 3 subunits: alpha, beta, and gamma; 15 laminin isoforms; and binds to integrin
What is the function of laminin?
cell adhesion, differentiation, migration, signaling, and homeostasis
List other matricellular proteins in the ECM (6)
- thrombospondin-1
- thrombospondin-2
- osteonectin
- osteopontin
- osteocalcin
- tenascin
What is the function of thrombospondin-1?
adhesive glycoprotein
What is the function of thrombospondin-2?
adhesive glycoprotein
What is the function of osteonectin?
Regulates cell growth through interactions with the ECM abd cytokines required for collagenin bone to become calcified.
What is the function of osteocalcin?
binds tightly to hydroxyapeptitie and calcium ion in bone and tooth
What is the function of osteopontin?
binds tightly to hydroxyapeptitie, important for calcium ion in bone and tooth
What is the function of tenascin?
migration of cell, binds to integran and syndecan
What is an integrin?
a transmembrane receptors that are the bridges for cell-cell and cell-ECM interactions; crosstalk with growth factors, cytokines, and MMPs
What are the properties of integrin?
- 120-140kDa
- a transmembrane receptor
- essential in embryonic development and survival
- 1/3 interact with ECM proteins through RGD
- GFFKR sequence (gly-phe-phe-lys-arg) in the cytoplasmic tail of the alpha subunit: involved in heterodimer assembly and regulation of ligand recognition
What happens if integrin was “knocked out?”
a) placental defects and embryonic hemorrhages
b) defects in epithelial adhesion to underlying basement membrame
c) bleeding disorders and defective osteoclastogenesis
d) mutation assoicated with gallbladder and breast cancer
What are the 4 categories of ligand specificity?
- RGD receptors
- Laminin receptors
- Leukocyte-specific
- Collagen receptors
More than 1 integrin can bind to a specific ligand and more than 1 ligand can bind to a specific integrin
What are the two major families of co-receptors/modifiers?
Syndecans
Tetraspanins
What is a syndecan?
a transmembrane protein that plays an important role in ECM interactions, cooperates with integrins, binds to a variety of ligands: fibronectin and interacts with growth factors
Resuls in inducing stable adhesion through mutifunctional cell-surface co-receptors
How does syndecan and integrin communicate?
crosstalk and signaling with cellular communication network factor-1
What is tetraspani?
a transmembrane protein; it attenuates bone growth and enhances bone marrow adipogenesis; also can promote multiple cancer stages
How is integrin activated?
- inside to out (intra to extracellular) - interacting with growth factors, cytokines and mediated with Talin/Kindlin
- outside to in (extr to intracellular) - binding to ligands
Brief description and genetic disease of collagen 1
- structural compoent of all tissues except cartilage
- osteogenesis imperfecta: extremely fragile bone
- autosomal dominant
Brief description and genetic disease of collagen 2
- predominant component of cartilage that mediates with proteoglycans
- stickler syndrome type 1: facial abnormalities and joint problems
- spondyloepiphyseal dysplasia: affects bones of the spine and the ends of long bones in arms and legs
Brief description and genetic disease of collagen 11
structural component of articular cartilage and modulates cartilage matrix homeostasis;; stickler syndrome type 2
Brief description and genetic disease of collagen 10
- a non-fibrillar collagen
- structural component of hypertrophic cartilage, regulates matrix mineralization, and compartmentalization of ECM components.
- Schmid-type metaphyseal chondroplasia: long bones will be short and curved, widened growth plates and metaphysis
- Osteochondritis dissecans: joint disorders in which cracks in the articular cartilage and subchondral bone in the joint
Brief description and genetic disease of fibrillin 1
- non-fibrous protein
- major structure of microfibrills; tissue homeostasis
- marfan syndrome: curvature of spine, aortic dilation or aneurysm
- atherosclerosis
Brief description and genetic disease of fibronectins
- involved in cellular adhesion and ECM assembly, tissue injury, and inflammation regulation of vascular morphogenesis including angiogenesis.
- Glomerulopathy
- Idiopathic pulmonary fibrosis
Brief description and genetic disease of laminins
- Involved in cell adhesion, migration and differentiation
- congenital muscular dystrophy
Brief description and genetic disease of integrins
- leukocyte adhesion deficiency (LAD) : due to mutation of beta2 integrin
