MCB Lecture 40 MAPK Pathway, RS/TK Flashcards
How are kinases in the MAPK pathway activated?
Phosphate is added to serine, threonine and tyrosine residues on the protein
Describe the MAPK pathway from Ras onwards
- Ras is activated by GEF
- Ras activates Raf (MAPKKK)
Raf activates Mek (MAPKK) - Mek activates Erk (MAPK)
- MAPK enter the nucleus and activates Immediate Early Response Genes
- IER genes are transcribed and translated eg. Myc
- Myc protein returns to nucleus and turn on Delayed response genes
- Delayed response genes (cyclins) are transcribed and translated
- Cyclin binds to Cdk
- Cdk-cyclin (active) phosphorylated Retinoblastoma, inactivating it
- Inactive Rb releases E2F
- E2F activates transcription of s phase cyclin
- Cell cycle stimulated
What are Immediate Early Response genes?
Myc
Fos
Jun
Rapidly transcribed, even in the absence of protein synthesis
What are Delayed response genes?
For example…?
Cyclins
These aphave their transcription activated by IER genes
Describe the role of positive feedback in the MAPK pathway
Cyclins feedback to Retinoblastoma, increasing its inactivation
E2F self promotes
What is the role of Retinoblastoma protein in the MAPK pathway?
It binds and inactivates E2F.
When itself inactivated, it releases E2F -> cell cycle
What is the role of E2F in the MAPK pathway?
Brings about transcription of s phase cyclins
Causes the cell cycle to progress from G1 to S
What are the features of Retinoblastoma? (3)
- Tumour suppressor gene
- Gate keeper of proliferation
- Requires two hits to become inactive
What are the types of ligands involved with Receptor Serine/Threonine Kinases?
Transforming Growth Factors
BMP
Activin/ inhibins
What are BMPs?
Bone morphogenic proteins
What are TGFbeta?
Transforming GF
These are ligands that act on TGFB receptors
Describe the activity of ligands in RSTKs
They are normally inactive. They require certain conditions to become active:
Acidic environment
Enzymes
Inflammation
Integrins
What are the three types of receptor serine Threonine kinases?
Differentiate between their function
Type I
Type II
Type III: non signalling, present ligands to type II
Describe signal transduction in Receptor Serine Threonine Kinases
- Ligand binds to TbetaR type II
- Type II receptor is phosphorylated
- Type II receptor recruits and phosphorylates the Type I receptor.
- Smads are recruited and activated by Type I
What are the three different types of Smads?
Receptor Smads: bind to type I receptor and are activated
Common Smad: bind to R Smad to activate transcription
Inhibitory Smad: deactivate the r-Smad
Describe the role of Smads in signal transduction pathways in Receptor Serine Threonine Kinases
- Type 1 receptor serine threonine activates a receptor smad (type 3 or 2)
- Receptor Smad oligomerises with common Smad (4)
- Smad oligomer moves to the nucleus, binds with other transcription factors and activates gene transcription
Describe the function of SARA protein
SARA is involved in docking of SMADS to vesicles in the endocytosed of TGFB receptors
SARA recruits Smads, allowing for the successful delivery of TGFB from the cell surface to the nucleus
What is EMT?
Epithelial-Mysenchymal Transition
For cancerous cells to become mobile, they must lose their epithelial features so that they can migrate
What is Snail?
It is a protein that is activated by Smads
It then controls gene transcription
It up regulates mysenchymal genes
It inhibits transcription of epithelial genes
What epithelial markers are inhibited by Snail?
- Actin ring
- Cell-cell junctions, cadherin synthesis
- Apical basso lateral polarity
What mysenchymal markers are upregulated by Snail?
Production of ECM protein
Migration
Describe the formation of cataracts in rats
When a transgene with increase TGFB receptor activity is put in the eye of rats, cataracts form.
What does overproduction of TGFbeta induce in rats?
ECM protein synthesis
Migration
Cell proliferation
Mysenchymal gene transcription
How is Retinoblastoma inactivated?
It is phosphorylated
Which cyclin gene is turned on by Myc?
Cyclin D
A G1 cyclin
Which cyclin gene is turned on by E2F?
S phase cyclin
Cyclin E
Cyclin A
Which receptor is responsible for EMT?
Receptor serine threonine kinase
Which are the receptor Smads?
Smads 2 or 3
Which are the common Smads?
Smad 4
Which are the inhibitory Smads?
Smads 6 or 7
Where does beta-catenin in the cell come from?
Adherens junctions as they are constantly assembled and disassembled
