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What are Enzyme Coupled Receptors?
Receptors with an Extracellular Ligand Binding Domain and an Intracellular Enzymatic or Enzyme Coupled Domain.
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How many Transmembrane segments to Enzyme-Coupled Receptors have?
One, generally.
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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.
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What are Receptor Tyrosine Kinases?
Kinases that specifically phosphorylate specific Tyrosines. Both on themselves and other molecules.
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What are Tyrosine-Kinase-Associated Receptors?
Receptors that have no intrinsic enzymatic activity but recruit Kinases to relay the signal.
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What are "Receptor-like" Tyrosine Phosphatases?
- Remove phosphate groups from specific intracellular tyrosines.
- Receptor-like because they have no identified ligands.
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What are some examples of Extracellular Signals acting through Receptor Tyrosine Kinases?
- Epidermal Growth Factor
- Platelet Derived Growth Factor
- Fibroblast Growth Factor
- Insulin
- Neurotrophins
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What are Ephrins?
Membrane bound ligands.
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What are some roles of Ephrins?
Guiding migration of cells and axons during development.
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What is special about Ephrins and their Receptors?
They can act as both Ligands and Receptors.
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What is Bidirectional Signlling?
When when a signal moves in both directions. E.g, one cell affects another but is affected itself too.
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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.
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What are Receptor Tyrosine Kinases responsible for Phosphorylating?
Themselves and specific Intracellular Targeting Proteins.
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What happens to Proteins Phosphorylated by Receptor Tyrosine Kinases?
They bind to the Receptor.
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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).
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What is Transautophosphorylation?
When multiple kinases dimerize and phosphorylate eachother.
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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".
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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.
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How do RTK's act like scaffold proteins?
Sometimes the phosphorylation of the CTD will bring the correct proteins together to relay the signal.
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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.
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How can different RTK's activate different intracellular responses?
By binding different proteins to their CTD.
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What is the structure of Insulin and IGF receptors?
- Transmembrane Tetramers.
- (Containing Two Kinase Domains)
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How does ligand binding affect Insulin and IGF receptors?
- By changing the shape of their transmembrane receptor chains.
- The Kinase domains move close together.
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What is the role of Insulin Receptor Substrate 1 (IRS-1)?
Location of Phosphotyrosine for docking of signalling proteins to the Insulin receptor complex.
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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.
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What do Sarc Homology (SH2) domains bind to?
Phosphotyrosine
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What are some enzymes involved in RTK docking?
- Phospholipase-C (Ca2+)
- Src (Kinase)
- Phosphoinositide 3-Kinase (Acts on lipids, better docking).
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What is the Src Protein?
Src: Proto-oncogene tyrosine protein kinase.
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How do proteins bind to the Phosphotyrosines in RTK?
- SH2 Domains
- Phosphotyrosine Binding Domains
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Do all proteins on bound to RTK's relay signals?
No, some decrease it by negative feedback.
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Give an example of a negative feedback protein on RTK.
The c-Cbl protein acts by Monoubiquitinylation.
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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.
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Give an example of Monoubiquitinylation in receptor deactivation?
Receptor Down regulation.
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What can result from mutations in the c-Cbl gene?
Cancer, due to prolonged RTK signalling.
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What type of G-Protein makes up the Ras Superfamily?
Monometic G-Proteins
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What two G-Protein Superfamilies relay messages from receptors to the intracellular environment?
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How do Ras and Rho act as Signalling hubs?
By spreading the siganl amongst different pathways.
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What are the three Human Ras proteins?
H-, K- and N-Ras
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Ras proteins are known to be Cytosolic, however where in the cell would you find them?
On the Plasma Membrane.
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How do Ras proteins bind to the Membrane?
One or More covalently attached lipid anchors.
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What is the result of Hyperactive mutant Ras proteins?
Tumors (Cancer)
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What does Ras-GAP stand for?
Ras-Guananine Activating Protein
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How do RTKs activate Ras?
Through indirectly coupled GEFs.
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What is "Bride-of-Sevenless"
A Drosophila gene encoding the Ligand for the Sev RTK.
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What is the Scructure of the Bride-of-Sevenless ligand?
A Seven Pass transmembrane protein.
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What is the Sev protein?
A protein found in the eye of developing drosophila
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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.
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Is Ras used in R7 differentiation?
Yes, it is essential.
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What is the "Son-of-Sevenless" gene?
A Gene encoding Ras-GEF.
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What are the Extracellular signals for Enzyme-Linked receptors called?
Growth factors
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