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What are Enzyme Coupled Receptors?
Receptors with an Extracellular Ligand Binding Domain and an Intracellular Enzymatic or Enzyme Coupled Domain.
How many Transmembrane segments to Enzyme-Coupled Receptors have?
What are the Six types of Enzyme-Coupled Receptor?
- Receptor Tyrosine Kinases
- Tyrosine-Kinase-associated receptors
- Receptor Serine/Threonine Kinases
- Histidine-Kinase-Associated Receptors
- Receptor Guanylyl Cyclases
- "Receptor-like" Tyrosine Phosphatases.
What are Receptor Tyrosine Kinases?
Kinases that specifically phosphorylate specific Tyrosines. Both on themselves and other molecules.
What are Tyrosine-Kinase-Associated Receptors?
Receptors that have no intrinsic enzymatic activity but recruit Kinases to relay the signal.
What are "Receptor-like" Tyrosine Phosphatases?
- Remove phosphate groups from specific intracellular tyrosines.
- Receptor-like because they have no identified ligands.
What are some examples of Extracellular Signals acting through Receptor Tyrosine Kinases?
- Epidermal Growth Factor
- Platelet Derived Growth Factor
- Fibroblast Growth Factor
What are Ephrins?
Membrane bound ligands.
What are some roles of Ephrins?
Guiding migration of cells and axons during development.
What is special about Ephrins and their Receptors?
They can act as both Ligands and Receptors.
What is Bidirectional Signlling?
When when a signal moves in both directions. E.g, one cell affects another but is affected itself too.
What property of Ephrin allows it to engage in Bidirectional signalling?
- Ephrin and it's receptor can act as a Ligand (as well as a receptor simultaneously).
- Ephrin is Membrane Bound.
What are Receptor Tyrosine Kinases responsible for Phosphorylating?
Themselves and specific Intracellular Targeting Proteins.
What happens to Proteins Phosphorylated by Receptor Tyrosine Kinases?
They bind to the Receptor.
How does an Extracellular Ligand Activate the Intracellular Kinase domains found in Receptor Tyrosine Kinases (RTK)?
Ligand Binding causes dimerization of two RTK's which activate and cross-phosphorylate eachother (Transautophosporylation).
What is Transautophosphorylation?
When multiple kinases dimerize and phosphorylate eachother.
How is transautophosphorylation of RTK's taken advantage of to study cells?
Because RTK's must form dimers to work properly, if one of the complex has a malfunctioning Kinase site, the protein will effectively be "switched off".
How does cross-phosphorylation aid in the signaling activity of Receptor Tyrosine Kinases (RTK)?
- Phosphorylation of the Kinase site increases Kinase activity.
- Phosphorylation of the CTD creates high affinity docking sites for signal proteins.
How do RTK's act like scaffold proteins?
Sometimes the phosphorylation of the CTD will bring the correct proteins together to relay the signal.
Do signalling proteins always have to interact with the Kinase region of the RTK to become phosphorylated?
- No, Signalling Proteins docked to the CTD can also be phosporylated.
- Not all docked Signalling proteins require phosphorylation however.
How can different RTK's activate different intracellular responses?
By binding different proteins to their CTD.
What is the structure of Insulin and IGF receptors?
- Transmembrane Tetramers.
- (Containing Two Kinase Domains)
How does ligand binding affect Insulin and IGF receptors?
- By changing the shape of their transmembrane receptor chains.
- The Kinase domains move close together.
What is the role of Insulin Receptor Substrate 1 (IRS-1)?
Location of Phosphotyrosine for docking of signalling proteins to the Insulin receptor complex.
How does Insulin and IGF signalling work?
Extracellular Signal (Insulin/IGF) -> Receptor -> Conformational change of receptor -> Transautophosphorylation of Kinase domains -> Phosphorylation of IRS-1 -> Docking of Signal Proteins.
What do Sarc Homology (SH2) domains bind to?
What are some enzymes involved in RTK docking?
- Phospholipase-C (Ca2+)
- Src (Kinase)
- Phosphoinositide 3-Kinase (Acts on lipids, better docking).
What is the Src Protein?
Src: Proto-oncogene tyrosine protein kinase.
How do proteins bind to the Phosphotyrosines in RTK?
- SH2 Domains
- Phosphotyrosine Binding Domains
Do all proteins on bound to RTK's relay signals?
No, some decrease it by negative feedback.
Give an example of a negative feedback protein on RTK.
The c-Cbl protein acts by Monoubiquitinylation.
How does c-Cbl and Monoubiquitinylation work?
- C-cbl adds single Ubiquitin residues to one or more sites on the receptor.
- Proteins containing Ubiquitin-Interaction motifs guide the protein to clathrin coated vesicles.
- The vesicles then head to Lysosomes.
Give an example of Monoubiquitinylation in receptor deactivation?
Receptor Down regulation.
What can result from mutations in the c-Cbl gene?
Cancer, due to prolonged RTK signalling.
What type of G-Protein makes up the Ras Superfamily?
What two G-Protein Superfamilies relay messages from receptors to the intracellular environment?
How do Ras and Rho act as Signalling hubs?
By spreading the siganl amongst different pathways.
What are the three Human Ras proteins?
H-, K- and N-Ras
Ras proteins are known to be Cytosolic, however where in the cell would you find them?
On the Plasma Membrane.
How do Ras proteins bind to the Membrane?
One or More covalently attached lipid anchors.
What is the result of Hyperactive mutant Ras proteins?
What does Ras-GAP stand for?
Ras-Guananine Activating Protein
How do RTKs activate Ras?
Through indirectly coupled GEFs.
What is "Bride-of-Sevenless"
A Drosophila gene encoding the Ligand for the Sev RTK.
What is the Scructure of the Bride-of-Sevenless ligand?
A Seven Pass transmembrane protein.
What is the Sev protein?
A protein found in the eye of developing drosophila
How is the Sev Protein activated?
- 1. The "Bride of Sevenless" ligand on an adjacent (R8) membrane interacts with with a Sev-RTK on the protein.
- 2. Sev-RTK induces Sev which triggers the cell to differentiate to an R7 cell.
Is Ras used in R7 differentiation?
Yes, it is essential.
What is the "Son-of-Sevenless" gene?
A Gene encoding Ras-GEF.
What are the Extracellular signals for Enzyme-Linked receptors called?