PI3K

Question 1

How can PI3Ks become activated by growth factors?

Answer 1

p85 binds to receptor via SH2 domain, activating the catalytic domain. Binding of Ras to PI3K activates catalytic domain. (Ras has very little activation of p110B.)

Question 2

PI3K lipids remain in the membrane - how do they signal?

Answer 2

Bind lipid binding domains (PH) found in a variety of proteins.

Question 3

How is mTORC1 affected by nutrient levels and hypoxia?

Answer 3

Low ATP sensed by increase AMP:ATP ratio.
AMPK phosphorylates TSC2 (at one site) –> drives formation of Rheb inactive state.
AMPK phosphorylates Raptor - causes 14-3-3 binding –> mTORC1 inhibition through allosteric mechanisms.

Stress –> TOR signalling inhibited.

Question 4

How do AAs affect mTORC1?

Answer 4

Activate it via inhibition of TSC1-TSC2 or via Rheb stimulation.

Question 5

How is S6K affected by the pathway?

Answer 5

Activated by mTORC1 by phosphorylation. Activates S6 subunit of 40S of ribosome –> enhances mRNA translation.
Also, inactivates mTORC2.

Question 6

What are the most frequently observed PI3K mutations?

Answer 6

E542K / E545K (blocks regulation)

H1047R (activated enzyme)

Question 7

How do we know PTEN is such an important tumour suppressor?

Answer 7

Mutations found in many sporadic cancers e.g. globlastoma, endometrium. prostate, breast.
+/- mice develop auto-immunity and cancer with 100% penetrance.

Question 8

What is Zydelig?

Answer 8

First clinical PI3K inhibitor. July 2014 US FDA approved.
Treat patients with relapsed follicular B cell lymphoma and relapsed small lymphocyte lymphoma.
Treat patients in combination with rituximab for CLL.

Question 9

What is Temsirolimus?

Answer 9

‘Torisel’, binds FKBP12 and inhibits mTOR. Approved for patients with advanced metastatic renal carcinoma but not supported by NICE (2010).