Chapter 8

Question 1

Name 5 factors controlling cell regulation?

Answer 1

Growth factors, cytokines, antigen stimulation, cell to cell contact, extracellular matrix

Question 2

Name the most common growth factor receptors?

Answer 2

EGFR, IGF-1R, FGFE, PDGFR, VEGFR, MET, RON, SEA, TRK, TIE, EPH/ECK/EEK/ERK/EIK/ROS/RET/ALK

Question 3

What happens to a TKR when bound by ligand?

Answer 3

Dimerisation and relief of the repressed confirmation, it will autophosphorylation of tyrosine residues. This will create docking sites and recruitment of intracellular substrates essential for signal propagation

Question 4

How can abnormal TKR signalling occur?

Answer 4

By downregulation of regulatory mechanisms such as becoming ligand independent.

Question 5

What is the effector proteins activated by GTP-bound RAS?

Answer 5

RAF, RAL and the p110 unit on PI3K

Question 6

How is RAS activity terminated?

Answer 6

By hydrolysis of GTP to GDP

Question 7

Name the 3 distinct MAPK pathways characterised?

Answer 7

ERK1/2, JNK/SAPK, p38

Question 8

Which GF are known to activate the ERK kinase pathway?

Answer 8

EGF, PDGF, FGF, cytokine receptors and antigen receptors

Question 9

What are phosphoinositides?

Answer 9

They are phospholipids of cell memnranes that are dynamically regulated in response to cell signalling.

Question 10

How does phosphoinositides contribute to signal propagation?

Answer 10

by two mechanisms: be precursors of the second messenger DAG and IP3 or by binding to signal molecules

Question 11

What is the negative regulator of PI3K signalling?

Answer 11

PTEN

Question 12

What’s the function of the following proteins: PIP2, PIP3, IP3K and IP3

Answer 12

PIP 2- membrane bound phospholipid activated by phospholipase C. PIP 3 is produced from PIP2 after enzyme activity by PI3K which facilitate formation of PIP3. IP3 is a second messenger formed from PIP2 together with DAG by phospholipase C. The result is release of intracellular calcium.

Question 13

What does PIP3?

Answer 13

Activates PDK1 and AKT, which are serine/threonine kinases.

Question 14

Explain signalling transduction in the cell after TK-activation?

Answer 14

The receptor undergo conformational change, autophosphorylates allowing which allow exposure of protein docking sites and enhanced catalytic activity. Proteins with tyrosine binding motifs such was SH2, PTB form a complex which is essential for protein complex formation. This can activate different intracellular paths such as RAF, IP3K and RALGDS = increased trascription of genes regulating cell-cycle progression, survival mm

Question 15

How is RAS activity important in human malignancy?

Answer 15

Abnormal RAS activity has been documented in 30% of human malignancies, either caused by mutations, or due to deregulated inhibitor signals upstream.

Question 16

Explain the MAP-kinase pathway?

Question 17

What is the consequence of altered growth stimulus in cancer cells?

Answer 17

Many cancer cells have the ability to undergo G1 phase progression in absence of mitogenic stimulus such as GF (this is also the first Hallmark of cancer). Example- activation mutation in any of the growth factor signalling components upstream of G1 checkpoint control can lead to cyclin D accumulation which drive continue cell cycling. Another example is the ability to evade apoptosis despite limited supply of growth factors -

Question 18

How are will growth factor signalling be suppressed in normal cells+

Answer 18

1) presence of enzymes that can eliminate docking sites for proteins- no formation of protein complexes or activation of downstream pathways
2) Modification of proteins with ubiquitin, resulting in degradation. This will eliminate activating enzymes from cytosol and prevent continued signalling

Question 19

JAK2 can activate which intracellular signalling pathways?

Answer 19

STAT
PI3K
ERK

Question 20

Draw the TK-receptor

Answer 20

age 175 in tannock

Question 21

Explain the activation of TKR;

Answer 21

Ligand bind - heterodimerization of the receptors allow conformational change and relief of the inhibitory constraints and autophosphorylation of the intracellular domains on turbine residues. The autophosphorylation sites works as both enhancers of catalytic activity and docking sites for intracellular signalling molecules.

Question 22

What are the 3 patterns activated by RAF-protein?

Answer 22

1. RAF pathway
2. IP3K
3. RALDGS

Question 23

Name the 3 most common MAP-kinase pathways;

Answer 23

1. ERK
2. c-JUN/SAPK
3. p38

Question 24

Give 4 examples of how a neoplastic cell can be self sufficient in cell signalling?

Answer 24

1. Increase GF signalling by either increased expression, attract CAMs, increase proteinases
2. Increase the expression of a recetor
3. Mutate the receptor resulting in continued phosphorylation
4. Loss of ubiquination of the receptors

Question 25

How are cytokine signalling propagated?

Answer 25

Ligand to receptor, receptor dimerisation resulting activation of intracellular JAK- which phosphorylates the GRB receptor unit and activate STAT- translocates to the nucleus and initiate trascription

Question 26

Which intracellular pathways are a part of integrin signalling?

Answer 26

1. RHO - cytoskeletal modification
2. ERK - cytoskeletal phosphorylation and transcription. ie cell growth
3. PI3K - survival and growth

Question 27

What are the 3 pathways of WNT signalling?

Answer 27

1. Canonical
2. WNT/planar cell polarity pathway
3. WNT/Ca pathway

Question 28

What are the target genes for WNT singalling?

Answer 28

c-MYC
cyclin D
Metalloproteinase 7

Question 29

What are ligands for NOTCH activation?

Answer 29

JAGGED and DELTA - will be on neighbouring cells

Question 30

How can the hedgehog pathway be activated in neoplasia?

Answer 30

1. Mutation in the pathway proteins - loss in PTC or GAIN of GLI or SMO
2. Activated via AKT or MEK
3. Activated through ligand mediated mechanisms by the tumour producing a HH like ligand

Question 31

How does the TGF-pathway work?

Answer 31

TGF- activate receptors, dimerzie causes phosphorylation and activation of the receptor which phosphorylates R-SMAD. R-SMAD interact with Co-SMAD and the complex accumulate in the nucleus. The complex interact with cofactors, that regulate transcription factors.

Question 32

Which factors inhibit TGF-beta signalling?

Answer 32

inhibitory SMADs and SMURFs

Question 33

By which two mechanisms can TGF-beta induce signalling?

Answer 33

Via SMAD or via RAS

Question 34

Which role does TGF-b have in cancer?

Answer 34

Dual role- dependent on the situation in can be inhibitory and promoting