Lecture 10 TGFbeta and FGF

Question 1

How do morphogens act

Answer 1

They act combinatorially to gradually define cell fates in the embryo

Question 2

2 examples of morphogens

Answer 2

Shh

Nodal

Question 3

How do some secreted signals that aren’t morphogens act

Answer 3

They exert only a local effect, without concentration-dependence

Question 4

Give an example of a non-morphogen, secreted signal and how it acts

Answer 4

FGF - acts to enhance proliferation and survival in the NT - for growth

Question 5

What does a signal refer to

Answer 5

The secreted protein/ligand itself

Question 6

What does signalling refer to

Answer 6

The signal transduction pathway operating in a receptive cell that responds to signal

Question 7

Give 2 examples of signal transduction pathways

Answer 7

• e.g. Shh initiates a signalling pathway which brings about Gli transcription in the nucleus (altering a balance between Gli activators and Gli repressors)
• e.g. Wnt signalling initiates a signalling pathway which brings about β-catenin transcription in the nucleus of Wnt responding cells

Question 8

3 common features of signalling pathways

Answer 8

Reception
Transduction
Response

Question 9

TGFbeta stands for

Answer 9

Transforming growth factor beta

Question 10

What sort of family is TGFbeta in

Answer 10

A superfamily

Question 11

Name the 3 TGFbeta families

Answer 11

• Activin family (which includes Nodal)
• TGFβ family
• BMP family

Question 12

What is meant by a superfamily

Answer 12

At the amino acid sequence level, and so genetic levels, these proteins are all quite similar

Question 13

How are members of the TGFbeta superfamily produced

Answer 13

all produced as a pro-protein, from which the pro- domain is cleaved during trafficking through the secretory pathway to leave the mature protein

Question 14

What does the pro-domain mediate

Answer 14

mediates the formation of homodimers and heterodimers i.e. these are formed before the proteins are exported from the cells

Question 15

What do different heterodimers and homodimers have?

Answer 15

Different biological activity

Question 16

What do the dimers interact to form

Answer 16

Activin receptors
TGFbeta receptors
BMP receptors

Question 17

What are the receptors also known as

Answer 17

ALK receptors

Question 18

What occurs when the receptors are stimulated by a ligand

Answer 18

The receptor kinases are activated to phosphorylate SMAD

Question 19

Which SMAD is phosphorylated by BMP

Answer 19

SMAD 1,5,8

Question 20

Which SMAD is phosphorylated by TGFbeta

Answer 20

SMAD 2,3

Question 21

What must occur for the SMAD to be activated

Answer 21

They must be phosphorylated

Question 22

Is phosphorylation alone sufficient for SMAD 1,5,8/2,3 to enter the nucleus

Answer 22

NO

Question 23

What else must occur for SMAD 1,5,8/2,3 to enter the nucleus?

Answer 23

They must be attached to SMAD4 which they do after phosphorylation

Question 24

What occurs after SMAD enters the nucleus with SMAD4?

Answer 24

They must bind to promotors and regulate transcription in the responsive cell

Question 25

Why are the 2 branches of the signalling pathway involving SMAD in competition?

Answer 25

There is only a limited amount of SMAD4 in the nucleus

Question 26

What is important in TGFbeta

Answer 26

cellular context

Question 27

How does TGFbeta act in cancer

Answer 27

TGFβ has a dual action in cancer as a tumour suppressor and a tumour promotor

Question 28

How is TGFbeta a tumour suppressor

Answer 28

TGFβ (the ‘proper’ one) inhibits tumorigenesis by inducing growth arrest (cell cycle arrest) and apoptosis (programmed cell death).

Question 29

How is TGFbeta a tumour promotor

Answer 29

TGF-beta induces tumour cell migration, and stimulates epithelial-to-mesenchymal transition.

Question 30

Why does it matter how TGFbeta acts in cancer

Answer 30

This is important for cancer therapies because giving TGFβ to supress the cancer, yet could actually worsen the cancer leading to more EMT/metastases.

Question 31

How can a molecule act as a cancer suppressor and promotor

Answer 31

In a normal cell, another SMAD (SMAD3) is phosphorylated by TGFβ signals, activating SMAD3 to allow it to bind with SMAD4 to enter the nucleus, binding to promoters to enable another protein to sit on the promoter, blocking transcription of the genes.
In a cancerous cell, though TGFβ signalling itself is not modified, other genes are, which means that TGFβ is phosphorylated an additional time. SMAD3 can bind to PCBP1 to enter the nucleus and act as a promoter for the transcription of genes which turn on CD44 transcription and promote EMT.

Question 32

What do FGF receptors form

Answer 32

Homodimer

Question 33

What helps FGF bind to its receptor

Answer 33

HSPG

It means there is a lot of attenuation in the matrix as it will easily bind to matrix components

Question 34

What is the FGF receptor linked to

Answer 34

Many kinases

Question 35

What does stimulation of FGF receptor lead to

Answer 35

stimulate one, two, or three distinct signalling pathways (ERK TF phosphorylation, CamKII phosphorylation, or PKB phosphorylation - each of these transcription factors will be phosphorylated in a response to differences in the molecules which are phosphorylated upstream of them).

Question 36

ERK activates genes involved in

Answer 36

proliferation and cell fate determination

Question 37

PKB activates genes involved in

Answer 37

survival

Question 38

CamKII activates genes involved in

Answer 38

morphology and migration