LM 7.5: Cell Motility

Question 1

why is cell motility important?

Answer 1

• to get to infection sites
• embryogenesis
• wound healing
• cancer

Question 2

what does cell linkage do?

Answer 2

facilitates adhesion, communication and linkage to the extracellular matrix

most cell linkages involve membrane receptors that then tie into the intracellular cytoskeletal filament system

Question 3

what are the types of cell junctions?

Answer 3

• adherens junction
• tight junctions
• gap junctions
• desmosomes

Question 4

what are non-junctional adhesions?

Answer 4

membrane receptors that don’t establish strong cytoskeletal linkages or structural linkages

they are very important for weak, transient adhesions

Question 5

which membrane receptors participate in non-junctional adhesions?

Answer 5

1. integrins
2. selectins - bind to carbohydrates on cell surface
3. cadherins
4. Ig-like cell adhesion molecules (CAMs)

Question 6

what are adherens junctions?

Answer 6

a type of junctional adhesion that are critical for forming epithelial sheets

they join the actin filaments of neighboring cells together

the anchor protein for adherens junctions are a family of proteins called cadherins

Question 7

what are cadherins?

Answer 7

the anchor proteins for adherens junctions

they are homodimers = one cell dimerizes with a cadherin on another cell

these cadherins then link into the actin cytoskeleton through linkages to yet other adherens junctions proteins

they help to make sheets of epithelial cells!

Question 8

what are tight junctions?

Answer 8

tight junctions between cells are connected areas of the plasma membrane that stitch cells together

Question 9

what are gap junctions?

Answer 9

clusters of channels that form tunnels of aqueous connectivity between cells

Question 10

what are hemidesmosomes?

Answer 10

they connect intermediate filaments of a cell to the basal lamina

the basal lamina is a combination of extracellular molecules on other cell surfaces

Question 11

what are desmosomes?

Answer 11

very strong connections that join the intermediate filaments of neighboring cells

Question 12

which receptors participate in cell to matrix adhesion?

Answer 12

interns

proteoglycan surface molecules

Question 13

how are individual cells in a epithelial sheet released?

Answer 13

for a cell that is part of a collective to migrate, it has to be released from the surrounding cells and the ECM

so what happens is cadherin disassembles to allow for release of individual cells

in the presence of Ca+2, cadherins form dimers but when Ca+2 is removed, the cadherins don’t bind and cell to cell adhesion is disrupted

Question 14

what modulates cadherin expression and adherens junctions?

Answer 14

epithelial-mesenchymal-transition modulates cadherin expression and adherens junctions

the EMT is typically where E-cadherin is lost! this unzips cell-cell adhesions and allows for escpape from the collective

EMT is the process that regulates single cells escaping epithelial sheets

this is how cancer cells begin their escape from the primary tumor!! aka metastasis!!

Question 15

what the difference between epithelial and mesenchymal cells?

Answer 15

epithelial cells –> mesenchymal via EMT

epithelial cells have cell polarity, cell-cell adhesion, they’re stationary, high levels of E-cadherin and low levels of N-cadherin

after the EMT you get mesenchymal cells

mesenchymal cells have no cell polarity, there’s loss of cell adhesion, they can migrate and invade other tissues, there’s low levels of E-cadherin and high levels of N-cadherin

Question 16

what types of junctions form cell-cell junctions?

Answer 16

1. adherens junctions

2. desmosome

Question 17

what types of junctions form cell-matrix junctions?

Answer 17

1. actin-linked cell-matrix junctions

2. hemidesmosome

Question 18

explain how adherens junctions work

Answer 18

cell-cell junction

cadherins are the transmembrane adhesion proteins that connect to cadherins on neighboring cells

cadherins are connected to actin filaments, which is their intracellular cytoskeletal attachment

Question 19

explain how desmosome junctions work

Answer 19

they’re cell-cell junctions

nonclassical cadherins like desmoglein and desmocollin connect to desmoglein/desmocollin on other cells

the nonclassical cadherins connect to intermediate filaments, which is their intracellular cytoskeletal attachment

Question 20

explain how actin-linked cell-matrix junctions work

Answer 20

they’re cell-matrix junctions

integrins/proteoglycans connect to ECM proteins

integrins are connected to actin filaments, which are their intracellular cytoskeletal attachment

Question 21

explain how hemidesmosome junctions work

Answer 21

cell-matrix junctions

α6β4 integrin and type XVII collagen connect to ECM proteins

α6β4 integrin and type XVII collagen are connected to intermediate filaments, which are their intracellular cytoskeletal attachment

Question 22

what is extravasation?

Answer 22

the process where immune and tumor cells exit the vasculature

the process of attaching to the endothelial lining followed by migration of cell through the vessel wall

starts when chemokine are released by immune cells at a site of injury which activates endothelial cells to express adhesion molecules –> WBC then attach to endothelial walls by rolling along the blood vessel walls

ex. leukocyte exits the bloodstream in response to signals generated by tissues that are infected or injured or inflamed

Question 23

what is diapedesis?

Answer 23

once the WBC sticks to the blood vessel wall, extravasated cells migrating or moving through the extracellular space to site of infection

Question 24

what are the general steps in extravasation?

Answer 24

1. capture
2. rolling
3. slow rolling
4. firm adhesion
5. transmigration

selectins are mostly present during the capture and rolling but then integrins kick in to firmly adhere and transmigrate the leukocyte to underlying chemoattractants secretes by tissues

Question 25

what are the specific steps in extravasation and which molecules are involved in each?

Answer 25

1. leukocytes just floating through the blood stream
2. endothelial cells receive a signal to being to activate - can come from chemokines from immune cells or from an injured cell
3. platelet activation factor and P-selectin are expressed on the endothelial surface
4. P-selectin grabs onto leukocytes by binding to S-lewis X, but this is a transient bond so this is why the leukocytes just roll along the blood vessel wall
5. leukocytes are activated and the PAF receptor on the leukocyte binds to PAF on the endothelial cell
6. integrin on leukocyte is fully activated and binds to ICAM (intracellular adhesion molecule) which arrests the leukocyte on the endothelial cell and polarizes it
7. leukocyte undergoes trans endothelial migration led by integrins and the secretion of enzymes that act like scissors to cut a path along the underlying tissue for cells to migrate upon - the leukocyte has lamellapodia or pseudopodia that push between adjacent cells

Question 26

what are integrins?

Answer 26

transmembrane proteins that bind ECM ligand and link the outside ECM to the cell’s actin cytoskeleton

Question 27

what is the structure of an integrin?

Answer 27

they are transmembrane proteins that are heterodimers made of one α and one β subunit

there’s an extracellular ligand binding domain and a cytoplasmic tail on the inside of the cell that will hook into the actin cytoskeleton

there’s tons of different α and β subunits and they all mix and match with each other - the specific dimer formed dictates which extracellular ligand it can bind

Question 28

what extracellular ligands can integrin bind?

Answer 28

there’s tons of different α and β subunits and they all mix and match with each other - the specific dimer formed dictates which extracellular ligand it can bind

possible ECM ligands: collagen, fibronectin, laminins, VCAMs

Question 29

how strong is integrin binding to its ECM ligands?

Answer 29

integrins usually have relatively low binding affinities for their ligand

it takes weak binding of numerous integrin molecules to give the cell a firm hold onto the ECM = clustering!!

this is actually helpful when it comes to cell migration because if the bonds were too strong the cell wouldn’t be able to move

Question 30

how are integrins activated?

Answer 30

signals are generated from either the inside of the cell or the outside of the cell

these signals tell the integrin to activate and change conformation so that it can bind its ligand

Question 31

what are focal adhesions?

Answer 31

linking the ECM to the intracellular cytoskeleton

Question 32

how hoes focal adhesion work?

Answer 32

once integrins cluster, the assemble a network of proteins on the inside of the cell, linking the integrin cytoplasmic tail with the actin cytoskeleton = focal complex

so forces exerted on the outside of the cells through compression of tissue can be transduced to the inside of the cell through the integrin-actin linkage which will cause the cell to alter cell signaling or gene expression to respond to its environment

Question 33

what happens if integrin mediated adhesion isn’t regulated effectively?

Answer 33

we need to make sure integrin mediated adhesion is working because it’s what allows the cell to adhere and move!

if this system is messed up, it’s usually due to mutations or defects in genes encoding integrins

Question 34

what is Glanzmann’s disease?

Answer 34

alpha II betaIII heterodimer is mutated/absent which leads to a defect in fibrinogen binding and lack of clotting

integrin on platelets is unable to bind to fibrinogen to participate in clotting! this is a disease effecting integrin!

this is a disease that effects integrin!

Question 35

what is LAD?

Answer 35

LAD = leukocyte adhesion deficiency

a variety of integrins including B1,2 and 3 are missing or mutated

this disallows cells from interacting with ECM proteins so these cells can’t be recruited to sites of injury or infection

Question 36

what is paracellular diapedesis?

Answer 36

migration between endothelial cells of the blood vessel into the tissue

Question 37

what is transcellular diapedesis?

Answer 37

migration through a pore in an individual endothelial cell of the blood vessel into the tissue

Question 38

intravasation vs. extravasation vs. diapedesis

Answer 38

intravasation = cell entering the blood stream through the endothelium

extravasation = cell leaving the blood stream through the endothelium

diapedesis = cell traveling through the endothelium to leave the blood stream into the tissue

Question 39

what is matrix-metalloproteases?

Answer 39

diapedesis usually requires molecular scissors called MMP to gain access to underlying tissues

the basement membrane is made up of ECM proteins that are tightly woven and hard to get though!

cells are much bigger than the holes in the basement membrane so they need to cut their way through with MMPs

MMPs are secreted enzymes that the tumor cells or immune cells spit out

MMPs digest basement membrane and ECM so that cells can gain access to underlying tissues

Question 40

how does a cell move forward through the endothelium when it’s trying to leave the blood stream?

Answer 40

contraction and tension!! it’s a traction driven model!!

1. leading edge extends in the form of an actin-enriched protrusion called a lamellipodia/filopodia
2. F-actin polymerization creates force to push upon the plasma membrane to deform it into an extension
3. the cell makes an integrin-dependent adhesive contact with the underlying substrate, via formation of focal contacts
4. rear end of the cell must disengage in order to allow for forward motion so focal contacts are severed and there’s a myosin II-based contraction even to snap the rear forward
5. further extension of the lamellapodia until the cell gets to where it wants to go

Question 41

what are migrasomes?

Answer 41

bits of migrating cells that are left behind on the substrate that can act as breadcrumbs to guide other migrating cells