Cell Interactions with the ECM

Question 1

T or F. The ECM regulates cell development, vitality, and behavior

Answer 1

T. One way cells know they are in the right place is vi their attachment to the ECM. Thus, a liver cell that somehow makes it way to muscle will not be able to attach to the ECM and will undergo programmed cell death as a result. In cancer metastasis, cancer cells ARE anchored in the right place but break these connections to travel to other areas of the body

Question 2

Describe the structure of elastin.

Answer 2

Elastin molecules form beta spring spirals which are hydrophobic in the normal relaxed state. When the heart beats, the hydrophobic elastin becomes surrounded by water so it expands to avoid contact with the water, thus increasing the diameter of the vessel. When the water passes, the elastin returns to its relaxed state. This structures is responsible for the elasticity of major arteries

Question 3

How is elastin strength improved?

Answer 3

elastin polypeptides are held together by crosslinks called desmosines to form a network

Question 4

Elastin crosslinks derive from which AA?

Answer 4

lysine and the aldehydes of lysine (called allysine) formed by lysyl oxidase. Four different polypeptide lysines come together to form a desmosine.

Question 5

What is fibronectin?

Answer 5

a CT glycoprotein that mediates many aspects of cell attachment in the ECM. Many binding capabilities. Completely extracellular

Question 6

What are the binding domains of fibronectin?

Answer 6

fibronectin exists as two molecules held together b disulfide bonds at the C terminus and contains binding sites for (from N terminus to C terminus):

1) self binding
2) collagen binding
3) cell binding (specifically integrins)
4) heparin binding (a proteoglycan)

Question 7

What sequence on the cell binding part of fibronectin is required for binding to integrin?

Answer 7

RGD (Arg-Gly-Asp)

Question 8

What are the major connections of the cell binding part of fibronectin?

Answer 8

1) fibronectin connects with integrin (an integral membrane protein) on one side via a RGD sequence on the fibronectin molecule (and then collagen and heparin on its other binding domains in the ECM)
2) Integrin passes through the cell membrane where it attaches to adaptor proteins on the inside of the cell
3) adaptor proteins then connect with actin inside the cell

Thus, extracellular connection to collagen and intracellular connection to actin via this fibronectin molecules add substantial stability to cells

Question 9

Describe the structure of integrin

Answer 9

2 polypeptides make up a single integral molecule, an alpha and a beta subunit. The extracellular part of both subunits bind to many extracellular proteins (fibronectin, laminin, etc.) while the internal parts bind mostly actin, talin, and filamin.

The alpha subunit actually consists of two parts held together by disulfide bonds (this bond occurs in the extracellular part of the subunit). The beta subunit has a cysteine rich strand on the outside of the cell

Question 10

What happens when something binds to integrin?

Answer 10

a conformational occurs in the subunits that causes the release of kinases on the inner side of the integrin that tells the cell it has attached. This signal is good for growth and stability

Question 11

How does binding of integrin to extracellular molecules (such as fibronectin) work?

Answer 11

An extracellular signal binds an an associated cell surface receptor which causes the integrin to change conformation in order to facilitate binding of the molecule to the integrin. Then the conformational change occurs that always the release of an internal signal from the integrin to the cell that tells the cell it has successfully binded

Question 12

What is Glanzman thrombasthenia caused by?

Answer 12

platelets lack a specific integrin (a2b3) so they can’t aggregate to clot to bleeding is increased/uncontrolled

Question 13

What is Leukocytes adhesion deficiency?

Answer 13

leukocytes are missing a specific integrin beta subunit that allow the leukocytes to grip to selectins on the endothelial surface of vessels in order to pass through the vessels into infected regions. So these people cannot fight infection as well

Question 14

T or F. Developmental/transcriptional controls regulate the kinds of integrins expressed by specific cell types

Answer 14

T

Question 15

How do epithelial cells bind to laminin (which makes up basal lamina)?

Answer 15

integrins expressed on the epithelial cells grip them to separate themselves from surrounding CT. Basal lamina is itself a specialized CT.

Question 16

What types of collagen is common in basal lamina?

Answer 16

type IV. the basal lamina consists of cross-linking ‘chicken’ wire’ looking strands that are stacked upon each other in a nonuniform wy in order to limit the size of parties passing through them. So in other words, its not likely that one ‘blanket’ of basal lamina would block passage of most molecules because the sieve size would be too large, but by stacking them at angles you can exclude most molecules

In the kidney, the basal lamina creates barrier allowing the kidney to retain large molecules and filter out smaller waste molecules

Question 17

Describe the structure of laminin

Answer 17

Triple helix protein of an alpha, beta and gamma helices. Has globular domains that can bind to cell surface proteoglycans, type IV collagen, integrins, etc. Not a collagen triple helix

Question 18

What are the components of the basal lamina?

Answer 18

laminin, type IV collagen, perlecan, and nidogen

Question 19

What are the steps of cancer metastasis?

Answer 19

Cancerous cells mutate and multiply, must pass through the layers of basal lamina by making proteases- matrix metalonases (surgeons would typically remove all these layers to prevent movement of the cancer), and can then move in vessels, and need to make integrins that allow to grip onto selectins on the endothelial cells in the vessels, and additional integrins in order to break through additional basal lamina and grip other cells in order to keep growing in another environment