L18: Cell Signalling Flashcards
What is the general principle of signal transduction in cells?
Signals, often occurring outside the cell, are transduced and interpreted inside the cell, allowing the cell to respond appropriately.
Name four main types of cell signalling based on distance.
- Endocrine: Long-distance (e.g., hormones like insulin).
- Paracrine: Signals to nearby cells.
- Neuronal: Via neurotransmitters.
- Contact-dependent: Direct cell-to-cell contact.
What role do receptors play in cell signalling?
Receptors detect specific signals and initiate signal transduction, converting the extracellular signal into an intracellular response.
How do the same signals elicit different responses in various cells?
Responses depend on the receptor type and intracellular machinery unique to each cell.
What happens to a cell if it receives no survival signals?
It undergoes apoptosis (programmed cell death).
Differentiate between fast and slow cellular responses to signals.
• Fast responses: Modify existing proteins (e.g., phosphorylation).
• Slow responses: Involve transcription and translation, requiring new proteins to be made.
What are protein kinases, and what do they do?
Protein kinases are enzymes that phosphorylate proteins on serine, threonine, or tyrosine residues, altering their activity or creating docking sites.
What is the function of GTPases in cell signalling?
GTPases act as molecular switches, cycling between an active (GTP-bound) and inactive (GDP-bound) state to regulate signalling pathways.
Describe G-protein-coupled receptors (GPCRs).
GPCRs are cell surface receptors that span the membrane 7 times and, upon activation by a ligand, signal through trimeric G-proteins to initiate cellular responses.
What are second messengers? Provide examples.
Second messengers amplify and distribute signals within the cell. Examples include cyclic AMP (cAMP) and calcium ions.
Outline the role of phospholipase C (PLC) in signal transduction.
PLC cleaves PIP2 into DAG (diacylglycerol) and IP3 (inositol triphosphate), which respectively activate protein kinase C and release intracellular calcium.
What is the significance of the Ras protein in cell signalling?
Ras is a GTPase that activates downstream kinases in the MAPK pathway, driving processes like cell proliferation.
What is receptor tyrosine kinase (RTK) signalling?
RTKs, activated by dimerisation and autophosphorylation upon ligand binding, recruit adaptor proteins to propagate intracellular signals.
What are examples of clinical applications derived from signalling pathway knowledge?
• Herceptin (trastuzumab): Targets HER2-positive breast cancer.
• Vemurafenib: Inhibits mutant BRAF in metastatic melanoma.
What are the three main types of cell surface receptors?
- Ion channel-coupled receptors.
- G-protein-coupled receptors (GPCRs).
- Enzyme-coupled receptors (e.g., receptor tyrosine kinases).
How does cortisol mediate its effects?
Cortisol, a steroid hormone, diffuses across the plasma membrane, binds to an intracellular receptor, and together they regulate gene transcription in the nucleus.
What is the role of nitric oxide (NO) in cell signalling?
NO diffuses across membranes, affecting smooth muscle cells to regulate vascular tone and blood pressure.
What is the function of cyclic AMP (cAMP) in signalling?
cAMP, generated from ATP by adenylyl cyclase, acts as a second messenger to activate protein kinase A (PKA) and regulate various cellular processes.
How is cAMP signalling terminated?
cAMP is degraded to AMP by cyclic AMP phosphodiesterase, switching off the signal.
Explain the concept of a kinase cascade using the MAPK pathway.
In the MAPK pathway:
• Ras activates Raf.
• Raf phosphorylates MEK.
• MEK phosphorylates ERK (MAPK).
• ERK activates transcription factors to promote cell cycle progression.
What are the two main outcomes of calcium signalling?
- Activation of calcium-responsive proteins like calmodulin.
- Regulation of processes like muscle contraction, secretion, and enzyme activity.
What happens during the activation of receptor tyrosine kinases (RTKs)?
Ligand binding causes dimerization of RTKs, activating their kinase domains, leading to autophosphorylation and recruitment of adaptor proteins.
What is the role of Grb2 in RTK signalling?
Grb2 is an adaptor protein that binds phosphorylated tyrosine’s on RTKs and recruits SOS, a Ras-activating protein.
Why is Ras commonly mutated in cancer?
Mutations in Ras often prevent its GTPase activity, locking it in an active state, leading to uncontrolled cell proliferation.
What are the products of phospholipase C (PLC) activity, and what do they do?
• DAG (diacylglycerol): Activates protein kinase C (PKC).
• IP3 (inositol triphosphate): Triggers calcium release from intracellular stores.
What is the function of protein kinase C (PKC)?
PKC phosphorylates various target proteins, regulating processes such as metabolism, gene expression, and cell motility.
What is the role of calmodulin in calcium signalling?
Calmodulin binds calcium, undergoes a conformational change, and activates target proteins or enzymes involved in signalling.
How do cells integrate multiple signalling pathways?
Cells use signalling proteins modified by multiple post-translational modifications (e.g., phosphorylation) to integrate inputs from different pathways into a coordinated response.
How does HER2 amplification affect breast cancer prognosis?
HER2 amplification leads to increased proliferation of breast cancer cells and correlates with a poor prognosis, treatable with Herceptin (trastuzumab).
What is vemurafenib, and what mutation does it target?
Vemurafenib is a drug targeting mutant BRAF in metastatic melanoma, inhibiting aberrant MAPK pathway activation.
What are examples of long-distance and local signalling in the body?
• Long-distance: Hormonal signalling, e.g., insulin.
• Local: Paracrine signalling, e.g., delta-notch signalling during cell differentiation.
What is the primary function of delta-notch signalling?
Delta-notch signalling ensures that neighbouring cells adopt different fates, such as during nerve cell differentiation.
What is the difference between hydrophobic and hydrophilic signalling molecules?
• Hydrophobic molecules (e.g., steroid hormones): Diffuse across membranes to bind intracellular receptors.
• Hydrophilic molecules: Bind to cell surface receptors as they cannot cross the membrane.
Why do cells require survival signals?
Survival signals prevent apoptosis, ensuring that cells remain functional.
How do cells produce rapid responses to signals?
Rapid responses use pre-existing proteins modified through mechanisms like phosphorylation.
What are two main enzymes that regulate phosphorylation states in proteins?
- Protein kinases: Add phosphate groups.
- Protein phosphatases: Remove phosphate groups.
What are the key steps in the activation of heterotrimeric G-proteins?
- Ligand binds GPCR, causing conformational change.
- GDP is exchanged for GTP on the alpha subunit.
- The alpha subunit dissociates from the beta-gamma complex, activating downstream targets.
What is the role of the beta-gamma complex in G-protein signalling?
The beta-gamma complex can interact with ion channels or other targets to propagate the signal.
How does acetylcholine act on different cell types?
• Heart muscle: Slows heart rate via GPCRs.
• Salivary glands: Triggers saliva secretion.
• Skeletal muscle: Causes contraction via a different receptor.
What is the effect of protein kinase A (PKA) activation by cAMP?
PKA phosphorylates target proteins, regulating processes like glycogen breakdown, transcription, and heart muscle contraction.
How does inositol triphosphate (IP3) function in calcium signalling?
IP3 binds to receptors on the endoplasmic reticulum, causing the release of stored calcium into the cytosol.
What is diacylglycerol (DAG), and what is its role in signalling?
DAG remains in the membrane and activates protein kinase C (PKC), which phosphorylates target proteins.
What is the significance of Ras conformational changes?
Ras changes shape upon GTP binding, allowing it to activate downstream effectors in pathways like the MAPK cascade.
What proteins are activated by Ras in the MAPK pathway?
- Raf (MAPKKK).
- MEK (MAPKK).
- ERK (MAPK), which enters the nucleus to regulate transcription.
What cellular processes does ERK regulate?
ERK phosphorylates transcription factors, driving gene expression required for cell cycle progression.
What are the two products of phosphatidylinositol 4,5-bisphosphate (PIP2) cleavage by phospholipase C?
- IP3: Mobilizes calcium.
- DAG: Activates PKC.
What is the significance of protein location in signalling pathways?
Many signalling proteins, such as Ras and G-proteins, are membrane-associated, which helps localize and regulate their activity.
What are post-translational modifications, and why are they important?
Modifications like phosphorylation or acetylation integrate multiple signals and determine a protein’s activity or interactions.
How does Herceptin (trastuzumab) work in HER2-positive breast cancer?
It blocks HER2 signalling and recruits the immune system to attack cancer cells.
What mutation does vemurafenib target, and in which cancer is it used?
Vemurafenib targets the BRAF V600E mutation, commonly found in metastatic melanoma.
What is the primary transduction step in signal transduction pathways?
It involves the initial transmission of a signal from the outside of the cell through the plasma membrane via a receptor.
How do steroid hormones like cortisol enter cells, and what do they affect?
Steroid hormones diffuse across the plasma membrane, bind intracellular receptors, and regulate gene transcription.
How does nitric oxide (NO) affect vascular tone?
NO diffuses into smooth muscle cells, altering their contractility and thereby regulating blood pressure.
What is the function of primary messengers compared to second messengers?
• Primary messengers: External signals that bind receptors (e.g., hormones, neurotransmitters).
• Second messengers: Intracellular molecules like cAMP and calcium that amplify and distribute the signal.
How does protein phosphorylation affect protein function?
Phosphorylation can change protein conformation, alter its activity, or create docking sites for other proteins.
What is a key difference between protein kinases and protein phosphatases?
Kinases add phosphate groups to proteins, while phosphatases remove them, both regulating protein activity.
What role does the alpha subunit of heterotrimeric G-proteins play?
The alpha subunit binds GDP/GTP and, when activated (GTP-bound), separates from the beta-gamma complex to propagate signals.
Describe an example of a G-protein signalling pathway that involves ion channels.
In heart cells, the beta-gamma complex of a G-protein opens potassium channels, slowing the heart rate.
What are two main types of molecules that activate GPCRs?
GPCRs can be activated by a wide variety of ligands, including peptides, small molecules, and even light in the case of rhodopsin.
What is the role of calcium as a second messenger?
Calcium regulates processes like muscle contraction, secretion, and activation of calcium-responsive proteins like calmodulin.
What is the importance of the Ras-MAPK pathway in cell signalling?
It regulates cell proliferation by transmitting signals from receptor tyrosine kinases to transcription factors in the nucleus.
How does the activation of Ras occur?
A guanine exchange factor (e.g., SOS) facilitates the exchange of GDP for GTP on Ras, activating it.
What is the role of the adaptor protein Grb2 in RTK signalling?
Grb2 binds phosphorylated tyrosines on RTKs and recruits SOS to activate Ras.
How do receptor tyrosine kinases (RTKs) initiate intracellular signalling?
Ligand binding induces dimerization and autophosphorylation of RTKs, creating docking sites for signalling proteins.
What are PIP2, IP3, and DAG, and how are they related?
PIP2 is a phospholipid cleaved by phospholipase C to produce IP3 and DAG, which act as second messengers.
How does IP3 contribute to intracellular calcium release?
IP3 binds to receptors on the endoplasmic reticulum, opening calcium channels and releasing stored calcium into the cytosol.
What is the importance of diacylglycerol (DAG) in signalling?
DAG activates protein kinase C (PKC), which phosphorylates various substrates to regulate cell functions.
Why is calcium signalling visualized as a wave during fertilization?
Calcium release spreads across the egg, ensuring uniform activation and cellular changes necessary for development.
What is the functional significance of calmodulin in calcium signalling?
Calmodulin binds calcium, changes conformation, and activates target proteins, playing a critical role in signal transduction.
What is the function of phospholipase C in the context of G-protein signalling?
Phospholipase C cleaves PIP2 into DAG and IP3, which together trigger further signalling cascades.
Why is Ras considered an oncogene?
Mutations in Ras prevent it from hydrolyzing GTP, locking it in an active state and driving unregulated cell division.
What is the significance of phosphorylation in signal integration?
Phosphorylation integrates multiple signals by modifying proteins to create complex cellular responses.
How is the MAPK pathway involved in cancer therapy?
Drugs like vemurafenib target mutations in components like BRAF to block abnormal MAPK signalling in cancers like melanoma.
What is the role of protein kinase C (PKC) in signalling?
PKC, activated by DAG and calcium, phosphorylates various proteins, influencing cell growth, differentiation, and apoptosis.
How do growth factors influence receptor tyrosine kinases (RTKs)?
Growth factors bind RTKs, causing dimerization and phosphorylation, which initiate downstream signalling pathways.
