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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?
What are the Six Classes of Enzyme-Coupled Receptor?
- Receptor Tyrosine Kinases
- Tyrosine Kinase-associated Receptors
- Receptor-like Tyrosine Phosphatases
- Receptor Serine/Threonine Kinases
- Receptor Guanylyl Cyclases
- Histidine Kinase-Associared Receptors
What is the Basic Structure of a Receptor Tyrosine Kinase?`
A Cytosolic Kinase Domain and Highly Variable Receptor-Domain outside the Cell.
How does Ligand Binding affect RTK's?
It activates the Kinase domain.
What is the Drk protein?
An Protein in R7 development binding to the RTK and Ras-GEF
How does Drk Interact with Ras?
SH3 Domains (Proline-Rich)
How does Drk interact with the RTK?
SH2 Domain (Phosphotyrosine)
What is the role of Ras in R7 development?
To relay the signal
What is the overall effect of BOSS on the R7 cell?
Regulation of Glucose and Fat Utilization.
What Are Eph receptors?
A Tyrosine Kinase that guides Cell Migration, Adhesion and Repulsion.
What is an Ephrin?
A Membrane Bound Ligand for the Eph Receptor
Which Receptor is capable or Bi-Directional Signalling?
How are Ephrins Tethered to the Membrane?
By a GPI anchor.
How does IRS-1 bind to The Insulin Receptor?
- Insulin causes Autophosphorylation of it's cytosolic region.
- The Phosphotyrosine Binding Domain of IRS-1 binds to the Phosphorylated Cytosolic Domain.
What is an Example of a Ras Independant Signalling Pathway?
The Insulin Pathway
Briefly Describe the Insulin Pathway.
- Insulin Binds to it's receptor
- IRS-1 Binds and to the receptor and Phosphorylates Inositol in the Membrane
- Protein Kinase B Binds to the Phoshpoinositide
- Protein Kinase B is phosphorylated and Inactivates GSK 3
What is GSK 3? (Insulin pathway)
A Glycogen Synthase
What is a Cytokine?
An extracellular signalling protein that acts as a local mediator in cell-to-cell communication
What are Janus Kinases?
Tyrosine Kinases associated with Cytokine Receptors
What are some ligands for Cytokine Receptors?
- Hormones (Growth Hormone)
What are STAT proteins in the JAK-STAT system?
- Signal Transducers and Activators of Transcription
- Latent Gene Regulatory Proteins (Only Migrating to the Nucleus when Activated).
What is the Erythropoietin Receptor's Ligand?
What is the Kinase associated with Erythropoietin signalling?
How is the Erythropoietin Receptor (And JAK2) Dephosphorylated (Short Term)?
- SHP1 Phosphatase binds to phosphotyrosines on the Receptor with it's SH2 domain.
- The phosphatase Domain then Dephosphorylates the JAK2 Kinase
How is the Erythropoietin Receptor Deactivated (Long Term)?
- The SOCS Protein SH2 Domain Binds to Phosphotyrosine on the Receptor and JAK Kinase
- The SOCS-Box Protein Recruits E3 Ubiquitin Ligase
- Down Regulation Occurs
What is the SOCS Protein?
- A Protein used in Long-Term receptor down regulation.
- Attracts E3 Ubiquitin Ligase
Where does the Epo-Receptor go after ubiquitinization?
To the proteosome to be degraded.
What is Ras?
A monomeric G-Protein
Where is Ras found?
- Connected to the plasma membrane
- Attached via a Farnesyl Lipid Anchor
What is one role of Ras?
Regulation of Cells into DNA synthesis
What is the effect of injecting Permenantly Active Ras into cells without growth factors?
Cell will move into S-Phase
What is required for a Cell to move into S-phase?
- Functional Ras protein
- Growth factors (PDGF+EGF) to activate Ras
How is Ras coupled to Receptors?
Through SOS proteins (GEFs) bound to the receptor by GRB2 (Adaptor Proteins)
Starting with Ligand Binding (Receptor). How is Ras activated?
Ligand binding -> Receptors Dimerize -> Receptor Autophosphorylation -> Binding of GRB2 (SH2 Domain) -> Binding (SH3) & Activation of SOS (GEF) -> Exhange GDP for GTP -> Dissociation of Active Ras
What does MAP stand for?
Mitogen Activated Kinase
What is a Mitogen?
An Extracellular Signal Molecule that signals cells to increase rapidly in numbers.
Name the mechanism that Ras uses to Activate MAP.
A Phosphorylation Cascade
Describe the Phosphorylation Cascade in MAP signalling. Start with the active Ras Protein.
Active Ras -> Activate MAP Kinase-Kinase-Kinase -> Phosphorylate (Activate) MAP-Kinase-Kinase -> Phosphorylate MAP-Kinase
What are the two potential outcomes of the MAP Phosphorylation Cascade?
- Changes in Protein Activity
- Changes in Gene Expression
Where is ATP used in the MAP-Phosporylation Cascade?
In all phosphorylation steps
What is the main conformational change in activated (Phosphorylated) MAP-Kinase?
Rotation of the Activation Lip
State one similarity in cell signalling between the Mating Response and Glycerol Synthesis?
They both undergo a Ras induced Phosphorylation Cascade
How are different signalling pathways kept separate?
What does MAP-Kinase do?
- Relays signals by phosphorylation
- Moves to Nucleus and Activates Transcriptional factors
What genes does MAP-Kinase activate?
- Immediate Early Genes
- G1 cyclins (cell cycle initiation)
How does MAP-Kinase regulate transcription?
Activates P90RSK -> Moves into Nucleus -> Activates (Phosphorylates) TCF -> TCF binds to SRE on gene
What is p90rsk?
- pp90 Ribosome S6 Kinase
- Activated by MAP-Kinase
- Activates (Phosphorylates) SRF
- SRFs bind to SRE region on Gene
TCF is activated by MAP-Kinase. What does TCF stand for?
Tumor Cytotoxic Factor
How does Ras assist in Plasma membrane docking?
By activating PI 3-Kinase which phosphorylates inostitol producing docking sites.
How can different Phosphoinositides (and therefore different pathways) be created?
Using different Kinases
What is the overall function of PI 3-Kinase?
Activation of siganlling pathways leading to cell growth and survival
Starting with an Activated Receptor B receptor complex, describe the activation of Protein-Kinase C using BTK.
Activated R-B Complex -> PI-3 Kinase Binding & Activation -> Phosphorylation of Inositol -> BTK & PLC-γ bind to phosphoinositides -> BTK Activates PLC-γ -> PLC-γ cleaves creating IP3 + Diacylglycerol
Starting with a Survival signal describe the pathway leading inhibition of Apoptosis.
Survival Signal -> Dimerized Autophosporylated RTK -> Activates (Phosphorylates) PI 3-Kinase -> Phosphorylates Inositol -> PDK1 & PKB Bind to Phosphoinosities (PH Domains) -> PDK1 Activates PKB -> Active PKB Dissociates -> PKB Phosphorylates the BAD complex -> Death Inhibitory Protein (BAD) is activated -> Apoptosis is inhibited.
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