ECM and Cell-Matrix interface

Question 1

Describe ECM.

Answer 1

a gel-like ground substance, non cellular component within all tissues and organs, consisting of:

• fibrous proteins
• non-fibrous glycoproteins
• proteoglycans
• water

Question 2

What is a significant characteristic of ECM?

Answer 2

provides a physical scaffolding that initiates biomechanical and biochemical signals required for cellular adhesion, cell division, migration, tissue remodeling, and repair and tissue development.

Question 3

The ECM is composed of mostly what kind of collagen?

Answer 3

type 1

Question 4

What are all the functions of ECM?

Answer 4

1. physical fxn: support tissues to maintain shape and flexibility
2. biochemical fxn: controls cell growth, differentiation, tissue. remodeling, repair. inflammation, and deposition of fat.
3. regulatory fxn: binding, integrating and controlling the presentation of growth factors and other igands to the receptor of the cells and initates signaling.
4. Homeostatic fxn: balance between matrix deposition and its degradation by MMPs
5. 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.
6. Loss of function: disruption to ECM network will result in loss of cell and tissue homeostasis and lead to diseases like cancer

Question 5

What are the generalizations of ECM proteins?

Answer 5

ECM proteins are secreted proteins. There are two different kinds of proteins: fiber forming and non-fiber forming

Question 6

What are examples of fiber-forming proteins? What is the function of fiber forming proteins?

Answer 6

collagen and elastins; providng structure and adhesive functions

Question 7

What is an example of non-fiber forming proteins?

Answer 7

Laminin and fibronectin

Question 8

What is fibronectin?

Answer 8

a glycoprotein presented as a dimer in plasma and dimer or multimeric form in ECM
- 230-270 kDa with 20 different isoforms

Question 9

What is the function of fibronecin?

Answer 9

• 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

Question 10

What is RGD tripeptide sequence?

Answer 10

a Arg-Gly-Asp sequence in fibronectin that is essential for collagen type 1 deposition which results in osteoblast and odontoblast mineralization.

Question 11

How does the ECM link to the cell?

Answer 11

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.

Question 12

What is laminin?

Answer 12

a major non-collagenous glycoprotein; a heterotrimer of 3 subunits: alpha, beta, and gamma; 15 laminin isoforms; and binds to integrin

Question 13

What is the function of laminin?

Answer 13

cell adhesion, differentiation, migration, signaling, and homeostasis

Question 14

List other matricellular proteins in the ECM (6)

Answer 14

1. thrombospondin-1
2. thrombospondin-2
3. osteonectin
4. osteopontin
5. osteocalcin
6. tenascin

Question 15

What is the function of thrombospondin-1?

Answer 15

adhesive glycoprotein

Question 16

What is the function of thrombospondin-2?

Answer 16

adhesive glycoprotein

Question 17

What is the function of osteonectin?

Answer 17

Regulates cell growth through interactions with the ECM abd cytokines required for collagenin bone to become calcified.

Question 18

What is the function of osteocalcin?

Answer 18

binds tightly to hydroxyapeptitie and calcium ion in bone and tooth

Question 19

What is the function of osteopontin?

Answer 19

binds tightly to hydroxyapeptitie, important for calcium ion in bone and tooth

Question 20

What is the function of tenascin?

Answer 20

migration of cell, binds to integran and syndecan

Question 21

What is an integrin?

Answer 21

a transmembrane receptors that are the bridges for cell-cell and cell-ECM interactions; crosstalk with growth factors, cytokines, and MMPs

Question 22

What are the properties of integrin?

Answer 22

• 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

Question 23

What happens if integrin was “knocked out?”

Answer 23

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

Question 24

What are the 4 categories of ligand specificity?

Answer 24

1. RGD receptors
2. Laminin receptors
3. Leukocyte-specific
4. Collagen receptors

More than 1 integrin can bind to a specific ligand and more than 1 ligand can bind to a specific integrin

Question 25

What are the two major families of co-receptors/modifiers?

Answer 25

Syndecans | Tetraspanins

Question 26

What is a syndecan?

Answer 26

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

Question 27

How does syndecan and integrin communicate?

Answer 27

crosstalk and signaling with cellular communication network factor-1

Question 28

What is tetraspani?

Answer 28

a transmembrane protein; it attenuates bone growth and enhances bone marrow adipogenesis; also can promote multiple cancer stages

Question 29

How is integrin activated?

Answer 29

1. inside to out (intra to extracellular) - interacting with growth factors, cytokines and mediated with Talin/Kindlin 2. outside to in (extr to intracellular) - binding to ligands

Question 30

Brief description and genetic disease of collagen 1

Answer 30

- structural compoent of all tissues except cartilage - osteogenesis imperfecta: extremely fragile bone - autosomal dominant

Question 31

Brief description and genetic disease of collagen 2

Answer 31

- 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

Question 32

Brief description and genetic disease of collagen 11

Answer 32

structural component of articular cartilage and modulates cartilage matrix homeostasis;; stickler syndrome type 2

Question 33

Brief description and genetic disease of collagen 10

Answer 33

- 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

Question 34

Brief description and genetic disease of fibrillin 1

Answer 34

- non-fibrous protein - major structure of microfibrills; tissue homeostasis - marfan syndrome: curvature of spine, aortic dilation or aneurysm - atherosclerosis

Question 35

Brief description and genetic disease of fibronectins

Answer 35

- involved in cellular adhesion and ECM assembly, tissue injury, and inflammation regulation of vascular morphogenesis including angiogenesis. - Glomerulopathy - Idiopathic pulmonary fibrosis

Question 36

Brief description and genetic disease of laminins

Answer 36

- Involved in cell adhesion, migration and differentiation | - congenital muscular dystrophy

Question 37

Brief description and genetic disease of integrins

Answer 37

- leukocyte adhesion deficiency (LAD) : due to mutation of beta2 integrin