L3 - Signalling

Question 1

Outline the signalling pathway for TGF-ß

Answer 1

RII recruits RI and phosphorylates it. RI phosphorylates R-Smad, R-smad interact with Co-SMad and with importin for nuclear import. Translocation of Smads into the nucleus. TF associates and activates target genes

Question 2

What are the methods of downregulation of TGFß signalling?

Answer 2

Ski and Sno act as repressors via HDAC and histone modification
A 3rd group of Smads prevent the phosphorylation of R-Smads

Question 3

What does STAT stand for?

Answer 3

Signal Transducers and Activators of transcription

Question 4

Give some examples of signalling proteins that act through the JAK-STAT pathway and what they cause

Answer 4

gamma-interferon - activates macrophages
alpha-interferon - increases cell resistance to viral infection
Erythropoeitin - stimulates the production of erthrocytes
Prolactin - stimulates milk production
Growth hormone - stiulates growth by inducing IGF1 production
GMCSF - stimulates the production of granulocytes and macrophages

Question 5

Outline the basic pathway for JAK-STAT signalling

Answer 5

Cytokine receptors bind to ligand –> Dimeriation and phosphorylation of activation lip tyrosines –> phosphorylation of additional tyrosine residues –> STAT phosphorylated by JAK kinase –> Dimerization –> Into nucleus

Question 6

What is the pathway for casein gene activation by prolactin?

Answer 6

JAK2 receptor –> dimerzes –> STAT5 –> dimerizes –> transcription

Question 7

Give some examples of receptor tyrosine kinases

Answer 7

EGF receptor
Insulin receptor
IGF receptor
PDGF receptors
MCSF 
FGF receptors
VEGF receptors
Eph receptrors

Question 8

Outline the sevenless pathway

Answer 8

Boss binds to sevenless —> adaptor protein drk binds –> GEF activation –> RAS activation –> downstream signals turning this cell into an R7 cell

Question 9

What is Ras?

Answer 9

A monomeric G-protein which acts as a molecular switch

Question 10

Outline the MAPK pathway

Answer 10

Ras –> Raf –> MAPKK –> Erk –> Changes in protein expression and changes in gene expresson

Question 11

How is specificity created in the Ras pathway?

Answer 11

Scaffold proteins link signalling elements to a particular complex/receptor

Question 12

Outline the PI3K pathway

Answer 12

TRK –> PI3K –> Increases IP3 –> recruitment of PDK1 and Akt to the membrane –> PDK1 and mTOR activate Akt –> Akt releases apoptosis inhibitory protein from Bad

Question 13

Explain how WNT signalling works

Answer 13

When there is no WNT present glycogen synthase kinase 3ß phosphorylates ß-Catenin targeting it for degradation by the proteasome.
When WNT is present it binds to Axin and Dishevelled meaning that GSK3ß can’t form a complex to phosphorylate ß-Catenin therefore it is free to go to the membrane combine with other Tfs and activate target genes.

Question 14

Outline how HH signalling works

Answer 14

When HH is not present the Ptc receptor inhibits the binding of Smo receptors to the membrane.
When HH binds to the Ptc receptor Smo is allowed to bind. This binds with Cas2 and Fu which inhibits SU therefore Ci is free to be imported into the nucleus and activate transcription of the required genes

Question 15

Outline the Notch signalling pathway

Answer 15

Activation of Notch receptor –> cleavage of extracellular domain by ADAM10TACE –> cleavage of intracellular domain by the gamma secretase complex –> IZ fragment moves to the nucleus where it associates with CSL -> gene activation