Catalytic receptors and nuclear receptors

Question 1

what are the two main classes of catalytic receptors?

Answer 1

1. receptor tyrosine kinases
2. guanylyl cyclase receptors

Question 2

Receptor tyrosine kinases (RTKs) are often associated with growth factors which control cell fate.

briefly state the steps involved in RTK activation

Answer 2

1. binding of the growth factors EGF (epidermal growth factor) causes the receptor to dimerise
2. the dimerisation of the receptors means the intracellular domains also come together allowing one of the receptors to phosphorylate the other this is called autophosphorylation
3. once phosphorylated the receptor becomes active and signalling proteins are recruited to the phosphorylated receptor domains using binding sites called SH2 domains, these signalling proteins can be enzymes that directly produce signals

Question 3

nuclear receptors are viewed in essence as regulated transcription factors

this is because instead of being located in the membrane they are located in the _________

Answer 3

cytoplasm

Question 4

the oestrogen receptor is an example of a nuclear receptor

briefly state the steps involved in activating this receptor

Answer 4

1. ligands diffuse across the membrane via oestrogen receptor proteins in the cytoplasm
2. These receptor proteins then translocate to the nucleus where they work by binding the DNA as dimers
3. this promotes transcription at specific target genes and so changes mRNA and protein synthesis

Question 5

the oestrogen receptor is a single polypeptide containing 3 structural domains

what are these three domains

Answer 5

1. activation function 1 (AF1) domain
2. zinc finger domain
3. activation function 2 (AF2)

Question 6

Once activated how does the Oestrogen receptor (ER) initiate transcription of certain elements

Answer 6

1. The ER dimer binds to a palindromic sequence in the DNA gene promoter called the oestrogen response element (ERE)
2. one part of the [palindrome is then recognised by each receptor in the dimer
3. bound ER complexes stabilise RNA pol binding, allowing transcription to occur

Question 7

• The formation of different sorts of ER complexes form can depend on the type of ligand occupying the ER

give an example of an ER antagonist and SERM (selective ER modulator)

Answer 7

Fulvestrant – ER antagonist (tissue independent)

Tamoxifen – ER SERM (treatment for oestrogen-dependent breast cancer)

Question 8

Tamoxifen can be an antagonist or agonist to ERs depending on the tissue it’s administered to

What is tamoxifens MOA in breast tissue?

Answer 8

tamoxifen in breast tissue

• Tamoxifen inhibits ER dependent proliferation
• Anti-tumour effect
• Tamoxifen acts as an ER antagonist

Question 9

Tamoxifen can be an antagonist or agonist to ERs depending on the tissue it’s administered to

What is tamoxifens MOA in bone tissue?

Answer 9

tamoxifen in bone tissue

• Tamoxifen-ER complexes recruit bone specific co-activator proteins
• Tamoxifen acts as an ER agonist, promoting transcription
• Helps prevent bone loss / osteoporosis