Flashcards in Molecular Mechanisms Of Enzyme Coupled Receptors Deck (18):
What do receptor tyrosine kinases do and how are they activated? What do the activated things promote?
1. They phosphorylate tyrosine residues on a specific set of substrate
2. Activated by secreted growth factors and hormones
3. They promote proliferation: vascular endothelial growth, insulin, platelet derived growth
What is the structure of ECRS and how are signals transduced across the plasma membrane?
1. ECRS are single alpha helices and span the membrane just once
2. It is dimerized or oligomerization of receptor subunits
3. This occurs when one or more add together which causes a reorientation of internal alpha helices (intrinsic activity) (kinase)
3. This calls a signal reaction and autophosphorylation
How does autophosphorylation cause biological effects?
1. An epidermal growth factor acts a dimer
2. Binds to receptor causes dimerization which causes reorientation of alpha helices
3. Intracellular kinases are activated which coverts ATP to ADP and phosphorylate some tyrosine residues
4. These acts within a receptor hence enzyme coupled receptors
5. Other signalling proteins bind onto the intracellular kinase domains which form many signalling complexes
How are signals generated by Epidermal growth factor?
1. GRB2 and SOS (regulate RAS) attach onto the kinases which activates RAS
2. RAS (kinase) converts GDP to GTP
3. RAS starts off a phosphorylation cascade from Raf1 to MEK to ERK- this requires ATP
Describe the process of how ERK (extracellular regulated protein kinases) translocate to the nucleus to promote gene transcription and cellular proliferation?
1. Epidemic Growth factor
2. MEK is active, it will act on ERK and phosphorylate it
3. It allows the opening of the nucleus to promote gene transcription and cellular proliferation
4. Acts on c-FOS which is a transcription factor that can turn on and off genes.
5. Phosphylate c-FOS which has more transcription factors
6. This can change gene transcription
7. Happens in hours or days
How does signalling work through the insulin receptor?
1. Insulin binds we get a re-ordering on intracellular kinase domains
2. Get activation of multiple intracellular cascade domains
How does insulin promote glycogen synthesis?
1. IRS-1 and PI3K bind onto the insulin which activates PIP2
2. This phosphorylates into the PIP3
3. The PIP3 turns into Protein Kinase D1 which turns into Akt
4. This turns into GSK3 which turns into glycogen synthase which becomes glycogen synthesis
5. Akt promotes the production of glucose transporters
What type of drugs can you create for EGF and why?
1. Anti cancer drugs as it prevents cellular proliferation which promotes production of the cancer
2. These drugs may be anti-EGF receptor antibodies or tyrosine kinase inhibitors
What are tyrosine kinase associated receptors?
1. They rely on the activity of cytosolic kinases to activate intracellular signalling cascades- so will bind to other proteins
2. Example is human growth hormone receptor- dimer bound to by HGH.
3. Cytosolic bind strongly to the C terminal tail
What are mammalian cytosolic tyrosine kinases?
1. They are a member of the Src family of protein kinases that are found tethered to the membrane and also to the receptor
2. They are important for protein to protein binding
3. They are all located on the cytoplasmic side of the cell- the SH2 and SH3 domains
4. Fixed in position by binding to the cell surface receptor and by covalent attachments to the lipid bilayer
What are cytokines, what roles do they play?
Give some examples of them?
1. Cytokines are large families of signalling molecules that includes chemokines, interleukins and tumour necrosis factor
2. They play roles in the regulation of the immune system- especially white blood cells but also endothelial cells
3. Cytokines regulate growth, maturation and the behaviour of subpopulations to immune cells
4. Important in determining how the body responds to infections and disease
What is a tumour necrosis factor?
1. Family of peptides that are a large family of cytokines
2. Best known member is the TNF-alpha which promotes apoptosis (cell death)
3. The TNF alpha exerts its biological effects by activating TNF receptor 1
How does Tumour necrosis factor (TNF) cause apoptosis?
1. TNF one receptor is a pre assembled trimer, that goes through oligamisation in TNF receptor 1
2. A large signalling complex is formed thorough proteins attaching onto the TNF receptor 1
3. Pro-caspase 8,10 goes to form caspase 8,10
4. Pro-caspase 3,6,7 forms Caspase 3,6,7 which leads to apoptosis
5. Too much TNF leads to necrosis and apoptosis
What are some TNF therapies used in society?
1. TNF can be responsible for the destructive inflammatory processes that occur in rheumatoid arthritis
2. Anti- TNFalpha therapies have been approved by the FDA for the treatment of Crohn's disease, psoriasis and ulcerative colitis
What are monoclonal antibodies used for?
1. Is an anti-TNF alpha and binds to it when TNF is in excess.
2. Infliximab is a chimeric (human and mouse) anti TNF-alpha monoclonal anti
3. Acts as a ligand
What are fusion proteins?
Proteins in a bacterium which acts as false receptors in the cell which mimics the receptor to prevent the binding of TNF to its cell surface receptor
Describe the receptor serine and threonine kinases?
1. They are mainly cytosolic
2. TGF beta family of proteins that activate serine/threonine kinase receptors
3. TGFBeta plays an important role in regulating the proliferation and differentiation of cells
4. TGFbeta is active as a dimer recruiting a hetero-tetrameric receptor complex
5. Similar to tyrosine kinase receptors but initiates a phosphorylation cascade that involves series and threonines