Receptor mechanism III Flashcards
What are growth factor receptors predominately?
• Predominantly single transmembrane domain receptors
What does the activation of growth receptors lead to?
Activation of receptor Kinases and multiple signalling pathways
Examples of tyrosine receptor kinase
Insulin
EGF or PDGF
What are jak/stat and what are they involved in?
○ chain of interactions between proteins in a cell
○ Growth hormone
Interferon
Example of serine threonine receptor kinase
○ TGFβ
What are enzyme linked receptors involved in the regulation of?
○ Cell growth ○ Division ○ Differentiation ○ Survival ○ Migration
Consequences of inappropriate activation of enzyme linked receptors
• Inappropriate activation is associated with disease particularly cancer
What does dimerization do when it comes to tyrosine activity?
• Dimerization brings two receptor molecules together allowing phosphorylation of specific tyrosine residues
Can all tyrosine residues be phosphorylated?
• Not all tyrosine residues can be phosphorylated
How are phosphotyrosine recognized and what does it lead to?
• Phosphotyrosine together with surrounding amino acids are recognised by SH2 domains of other proteins allowing them to bind and undergo activaiton
Result of the activation of tyrosine kinase receptors
• Activation of tyrosine kinase receptors activates multiple pathways
What do insulin receptors act on?
• Acts on liver and muscle to reduce blood glucose
What do insulin receptors consist of and how are they linked?
• Consists of 2alpha and 2beta subunits linked by disulphide bridges
What does the binding of insulin result in?
• Binding of insulin results in auto-phosphorylation of 2beta subunits
What does the activation of receptors lead to?
• Activation of receptors leads to activation family of small protein substrates called IRS
What does activated IRS activate?
○ IRS activates PI 3-kinase which activates PKB
What other substrates do insulin receptors recruit?
• Insulin receptor substrate also recruits other proteins such as Ras and Phospholipase C
What leads to the inactivation of receptor kinases?
• De-phosphorylation leads to inactivation
What are activated as a result of receptor activation?
Phosphates are activated
An example of a small G protein
Ras is one of a number of small G protein
What are small G proteins related to?
• Related to Gα subunit of cAMP
What are bound to small G proteins
Inactive GDP
When activated, what happens to small G proteins?
When active, it is replaced by GTP helped by GEF
What are small G proteins required for?
Growth, differentiation and cell motility
What activity do small G proteins contain?
• Contains GTPase activity, slow de-phosphorylation helped by GAP
What is slow de-phosphorylation helped by?
Helped by GAP
In how many percent of human tumors is mutated Ras found in?
30% of human tumors
What does the activity of Ras do?
Change GDP to GTP
What does activated Ras interact with?
Other proteins including Raf
What are activated Ras enhanced by?
Enhanced by GEF
What is activated Ras the docking site for?
Activated Ras is docking site for GTPase
What does activated GTPase lead to the removal of and what happens to the interaction between Ras and Raf/
• Activated GTPase leads to removal of phosphate to form GDP
○ RAS and Raf fall apart and is inactivated
What can mutations in key regulatory mechanism lead to ?
Can lead to cancer
What is Ras in cancers and what does it lead to?
Ras in cancers is mutated and leads to the loss of activity of GTPase
What does mutations in phosphatases lead to
It leads to the loss of phosphatases activity
Main issues in breast cancer
Over expression in breast cancer
What does Herceptin target and what is it used for?
Targets a member of the EGF receptor family and used for the treatment of some cancers
What do Jaks do to each other on tyrosines
Jaks cross phosphorylate each other on tyrosines
What do activated jaks do to receptors on tyrosine?
They phosphorylate receptors on tyrosines
What do STATS dock on to and what happens to them there?
Dock on phosphotyrosines and jaks phosphorylates them
What is STAT?
STAT is a transcription factor
What do STATs do once they’re phosphorylated?
STATs dissociate from the receptor and dimerize via SH2 domain
What do the dimers of STAT do?
• Dimer of STAT will bind to specific region of DNA and stimulate transcription of specific protein
What activates the smad-dependent signalling pathway?
TGF-beta
Basic overview of the smad-dependent signalling pathwat
- Receptor dimerizes
- Allows phosphorylation
- Smad 2 and 4 phosphorylated
- These then dissociate and are recognised and activated by Smad 4
- This will form a dimer that enters the nucleus and bind to specific regions of DNA leading to the transcription of specific genes.
