Cell Signalling and Cancer
42 Questions
0 Views

Choose a study mode

Play Quiz
Study Flashcards
Spaced Repetition
Chat to Lesson

Podcast

Play an AI-generated podcast conversation about this lesson

Questions and Answers

What is the primary role of the BCR-ABL fusion in chronic myeloid leukaemia?

  • Decreases tyrosine kinase activity
  • Inhibits cell growth and survival pathways
  • Activates ABL signalling pathways to promote cell survival and growth (correct)
  • Enhances normal cellular functions

    • What is the mechanism through which Imatinib inhibits BCR-ABL activity?

  • Binds irreversibly to the active site of the kinase
  • Stimulates normal tyrosine kinase activity
  • Inhibits RAS signaling pathways
  • Acts as a competitive inhibitor of ATP binding to the active site (correct)

    • What is a consequence of the (9;22) translocation in relation to BCR-ABL fusion?

  • Activation of SH3 regulatory domain
  • Formation of the Philadelphia chromosome (correct)
  • Conversion of chronic myeloid leukaemia into acute leukaemia
  • Inhibition of ABL signalling pathways

    • Which of the following best describes the resistance mechanism to Imatinib?

    <p>Development of point mutations within tyrosine kinase domain of BCR-ABL (C)</p> Signup and view all the answers

    What role does BCR play in the signalling pathways associated with BCR-ABL fusion?

    <p>BCR recruits ABL to cytoplasmic signalling pathways (C)</p> Signup and view all the answers

    What is the primary role of extracellular signals in cell behaviour?

    <p>They facilitate communication between cells to control behaviour and survival. (B)</p> Signup and view all the answers

    Which of the following signals primarily binds to cell surface receptors?

    <p>Hydrophilic signals (A)</p> Signup and view all the answers

    What is the main function of receptor signalling cascades?

    <p>To transmit and amplify external signals within the cell. (C)</p> Signup and view all the answers

    Which amino acid residues are primarily involved in phosphorylation?

    <p>Threonine, tyrosine, and serine (B)</p> Signup and view all the answers

    What is one of the STAR properties of signalling pathways?

    <p>They regulate cellular functions and amplify external signals. (D)</p> Signup and view all the answers

    What role do kinases play in cell signalling?

    <p>They catalyse phosphorylation of proteins. (C)</p> Signup and view all the answers

    Which effect is NOT typically associated with signalling pathways?

    <p>Reduction of cellular nucleus size (B)</p> Signup and view all the answers

    How do small hydrophobic signals interact with cells?

    <p>They directly pass through cell membranes and bind to intracellular receptors. (D)</p> Signup and view all the answers

    What happens to receptor tyrosine kinases (RTKs) upon growth factor binding?

    <p>They undergo dimerization. (A)</p> Signup and view all the answers

    What is the primary role of RAS in cell signaling?

    <p>To transduce signals downstream after activation. (C)</p> Signup and view all the answers

    Which of the following growth factors is known to bind to receptor tyrosine kinases?

    <p>Epidermal growth factor (EGF) (A), Transforming growth factor beta (TGFβ) (C)</p> Signup and view all the answers

    What is the consequence of trans-phosphorylation in receptor tyrosine kinases?

    <p>It activates further tyrosine kinase activity. (D)</p> Signup and view all the answers

    How does RAS become activated during the signaling process?

    <p>By exchanging GDP for GTP. (D)</p> Signup and view all the answers

    Which proteins are involved in the activation of downstream signaling after RAS activation?

    <p>Raf and Grb2 (B), MEK and ERK (D)</p> Signup and view all the answers

    What type of protein are GTPase-Activating Proteins (GAP) in the RAS signaling pathway?

    <p>Proteins that promote RAS inactivation. (C)</p> Signup and view all the answers

    What is one of the main functions of the MAPK pathway?

    <p>To drive cell growth. (D)</p> Signup and view all the answers

    What happens when receptor tyrosine kinases are switched off?

    <p>Cell growth is terminated. (C)</p> Signup and view all the answers

    Which mutation in RAS is most commonly associated with human cancers?

    <p>Point mutations at codons 12, 13, and 61. (C)</p> Signup and view all the answers

    Which of the following kinases is activated downstream of RAS?

    <p>MEK (C)</p> Signup and view all the answers

    Which molecule is responsible for turning RAS 'on' during signaling?

    <p>Sos (D)</p> Signup and view all the answers

    What is often a target for small molecule inhibitors in tumors?

    <p>Raf (A), MEK (B)</p> Signup and view all the answers

    How is apoptosis suppressed according to the PI3K pathway?

    <p>By activating AKT. (A)</p> Signup and view all the answers

    Which of the following correctly describes the role of PIP3 in the PI3K pathway?

    <p>PIP3 acts as a docking site for downstream proteins like PDK1 and AKT. (C)</p> Signup and view all the answers

    Which of the following is NOT a mechanism by which the cell can turn off the PI3K pathway?

    <p>Phosphorylation of AKT by PDK1 and mTORC2. (D)</p> Signup and view all the answers

    What is the primary effect of PTEN deletion in cancer cells?

    <p>Increased PIP3 levels, leading to sustained PI3K pathway activation. (C)</p> Signup and view all the answers

    Why are receptor tyrosine kinases (RTKs) often targeted in cancer therapy?

    <p>Mutations in RTKs are frequently found in cancer cells, leading to uncontrolled signaling. (B)</p> Signup and view all the answers

    Which of the following is a common mechanism by which cancer cells bypass the normal regulatory mechanisms of RTKs?

    <p>Increased expression of normal RTKs. (B)</p> Signup and view all the answers

    What is the primary mechanism by which Trastuzumab (Herceptin) exerts its therapeutic effect?

    <p>Promoting HER2 internalization and degradation. (C)</p> Signup and view all the answers

    What is the main difference between Trastuzumab and Pertuzumab in terms of their mechanism of action?

    <p>Trastuzumab promotes HER2 internalization, while Pertuzumab blocks HER2 dimerization. (A)</p> Signup and view all the answers

    Why are patients with KRAS mutations generally unresponsive to EGFR antibody therapy?

    <p>KRAS mutations activate an alternative signaling pathway that bypasses EGFR signaling. (C)</p> Signup and view all the answers

    What is the defining characteristic of the BCR-ABL fusion kinase?

    <p>The BCR-ABL fusion kinase is constitutively active due to the loss of the self-inactivation domain. (A)</p> Signup and view all the answers

    What is the key difference between the PI3K pathway and the BCR-ABL fusion kinase signaling pathway?

    <p>The PI3K pathway is activated by growth factors, while the BCR-ABL pathway is activated by mutations. (A)</p> Signup and view all the answers

    How does the Thr790Met mutation in EGFR lead to resistance to EGFR inhibitors like Erlotinib?

    <p>The mutation alters the binding site of the inhibitors, preventing effective binding. (D)</p> Signup and view all the answers

    What is the significance of the orphan receptor status of HER2?

    <p>HER2 does not require a ligand to activate downstream signaling. (B)</p> Signup and view all the answers

    Which of the following is NOT a characteristic of HER2 overexpression in breast cancer?

    <p>Increased sensitivity to EGFR inhibitors. (B)</p> Signup and view all the answers

    What is the primary mechanism by which Cetuximab and Panitumumab inhibit EGFR signaling?

    <p>They block ligand (EGF) binding to EGFR. (B)</p> Signup and view all the answers

    Which of the following is a key advantage of using targeted therapies in cancer treatment?

    <p>Targeted therapies have fewer side effects than traditional chemotherapy. (D)</p> Signup and view all the answers

    Flashcards

    BCR-ABL fusion

    A genetic alteration resulting from a translocation that leads to tyrosine kinase activation.

    Chronic Myeloid Leukaemia (CML)

    A type of cancer associated with the BCR-ABL fusion, leading to uncontrolled cell growth.

    Imatinib (Gleevec)

    A specific inhibitor of BCR-ABL tyrosine kinase used to treat CML.

    Tyrosine kinase activity

    An enzymatic activity that, when increased by fusion, promotes cell survival and growth.

    Signup and view all the flashcards

    Inhibitor resistance

    The phenomenon where some patients develop mutations that make BCR-ABL resistant to Imatinib.

    Signup and view all the flashcards

    Intracellular signalling

    Linked biochemical events connecting a stimulus with a response inside a cell.

    Signup and view all the flashcards

    Extracellular signals

    Signals that bind to receptors on the cell surface, triggering various responses.

    Signup and view all the flashcards

    Signalling molecules

    Molecules that bind to receptors, either inside or on the surface of cells to initiate signalling pathways.

    Signup and view all the flashcards

    EGFR signalling pathway

    A specific signalling pathway that influences growth and differentiation in cells.

    Signup and view all the flashcards

    STAR properties

    Shared properties of signalling pathways: Specificity, Transduction, Amplification, and Regulation.

    Signup and view all the flashcards

    Phosphorylation

    A process where kinases add phosphate groups to proteins, affecting their activity.

    Signup and view all the flashcards

    Kinases

    Enzymes that catalyse the addition of phosphate groups to proteins during phosphorylation.

    Signup and view all the flashcards

    Phosphatases

    Enzymes that remove phosphate groups from proteins, reversing phosphorylation.

    Signup and view all the flashcards

    Receptor Tyrosine Kinases (RTKs)

    Membrane-bound receptors that phosphorylate tyrosine residues when activated.

    Signup and view all the flashcards

    Dimerization

    The process where two RTK molecules come together upon activation.

    Signup and view all the flashcards

    Trans-phosphorylation

    When one RTK phosphorylates the other upon dimerization.

    Signup and view all the flashcards

    MAPK Pathway

    A signaling pathway that drives cell growth, activated by growth factors.

    Signup and view all the flashcards

    EGF (Epidermal Growth Factor)

    A growth factor that binds to RTKs, initiating the MAPK pathway.

    Signup and view all the flashcards

    Grb2 Protein

    A protein that binds to activated RTK and facilitates Ras recruitment.

    Signup and view all the flashcards

    Ras

    A G-protein that transmits signals for cell growth; often mutated in cancers.

    Signup and view all the flashcards

    GTPase Cycle

    The process where Ras binds GDP and exchanges it for GTP to activate signaling.

    Signup and view all the flashcards

    Raf

    A protein kinase activated by Ras that triggers further signaling.

    Signup and view all the flashcards

    Turning Off MAPK

    The mechanisms to deactivate the MAPK pathway and stop cell growth.

    Signup and view all the flashcards

    RAS Mutations in Cancer

    Mutations affecting RAS that lead to uncontrolled cell growth.

    Signup and view all the flashcards

    PI3K Pathway

    A signaling pathway that, when activated, leads to cell growth and survival.

    Signup and view all the flashcards

    Autophosphorylation

    The process where a receptor phosphorylates itself after activation.

    Signup and view all the flashcards

    Insulin Receptor

    A receptor that activates Tyrosine Kinase upon insulin binding, leading to PI3K recruitment.

    Signup and view all the flashcards

    PIP3

    A lipid product of PI phosphorylated by PI3K; recruits proteins like PDK1 and AKT.

    Signup and view all the flashcards

    AKT Activation

    Occurs when AKT is phosphorylated by PDK1 and mTOR, promoting cell growth.

    Signup and view all the flashcards

    mTORC1

    Part of the mTOR complex 1, stimulates cell growth by enhancing protein production.

    Signup and view all the flashcards

    PTEN

    A lipid phosphatase that dephosphorylates PIP3 to PIP2, turning off the PI3K pathway.

    Signup and view all the flashcards

    HER2

    A receptor that, when amplified, is linked to poor prognosis in breast cancer.

    Signup and view all the flashcards

    Trastuzumab

    An antibody used to target HER2 in breast cancer, promoting internalisation and cell death.

    Signup and view all the flashcards

    Erlotinib

    A small molecule inhibitor targeting EGFR for lung and pancreatic cancers.

    Signup and view all the flashcards

    BCR-ABL Fusion Kinase

    A constitutively active tyrosine kinase resulting from BCR and ABL gene fusion, leading to increased cell survival.

    Signup and view all the flashcards

    Gene Amplification

    Increased expression of a normal or mutated receptor, leading to heightened signaling.

    Signup and view all the flashcards

    Cetuximab

    An antibody that targets EGFR to block ligand binding, used in cancer therapy.

    Signup and view all the flashcards

    KRAS Mutation

    A mutation that makes patients non-responsive to certain EGFR inhibitors.

    Signup and view all the flashcards

    Study Notes

    Cell Signalling and Cancer

    • Cell signalling is a complex process linking stimuli to cellular responses. Communication between cells controls behaviour and survival.
    • Extracellular signals bind to receptors, triggering different intracellular signalling events. This can lead to quiescence/differentiation, proliferation, or blocking apoptosis.
    • Signal molecules can bind intracellularly or to cell surface receptors. Hydrophilic signals bind to surface receptors, while small hydrophobic signals directly bind intracellular receptors (e.g., steroid hormones).
    • Signalling pathways connect receptors and signalling molecules. Receptors transduce external signals into the cell, activating pathways regulating growth and differentiation (e.g., EGFR pathway).
    • Signalling pathways work through a cascade of protein activation, amplifying the initial signal to influence gene expression, metabolism, the cytoskeleton, and other cellular processes like cell cycle interruption, migration, angiogenesis, or apoptosis.

    Properties of Signalling Pathways

    • Signalling pathways share similar properties (STAR): Specificity (molecular interactions), Transduction across membrane, Amplification within the cell, and Regulation of cellular functions.

    Phosphorylation and Cell Signalling

    • Phosphorylation, catalysed by kinases, is a post-translational modification of proteins.
    • It occurs on threonine, tyrosine, and serine residues.
    • Phosphatases reverse phosphorylation, returning proteins to their normal state.
    • Phosphorylation creates binding sites for "reader" proteins, potentially increasing or decreasing protein activity.

    Growth Factors & Receptor Tyrosine Kinases (RTKs)

    • Growth factors (e.g., PDGF, EGF, Insulin, IGF, TGFα/β, NGF, VEGF, MCSF) bind to RTKs, which are membrane-bound receptors that phosphorylate tyrosine residues.
    • RTKs exist as monomers until activated, then dimerise.
    • Growth factor binding to RTKs causes a conformational change, dimerisation, and activation of tyrosine kinase activity in the cytoplasmic domain.
    • Trans-phosphorylation (autophosphorylation) further activates the kinase.

    Receptor Tyrosine Kinase Structure

    • RTKs have extracellular domains (binding site) and intracellular kinase domains.

    RTK Signalling Cascade

    • RTK activation triggers the recruitment of cytoplasmic proteins.
    • Recruited proteins get activated by tyrosine phosphorylation and further cell signalling events.
    • Different growth factor receptors can activate similar cytoplasmic pathways.

    Mitogen-Activated Protein Kinase (MAPK) Pathway

    • The MAPK pathway, activated by signals (e.g., EGF), promotes cell growth.
    • EGF binding to the EGF receptor activates downstream proteins(Grb2/Sos -> Ras).
    • RAS activation leads to a kinase cascade (Raf -> MEK -> ERK).
    • ERK activates transcription factors like c-fos, c-jun, c-Myc.
    • The pathway is switched off via signal removal, receptor deactivation, and downstream kinase dephosphorylation (using phosphatases).

    RAS

    • RAS genes code for G-proteins, crucial for signal transduction.
    • RAS is a membrane associated small GTPase, bound to GDP. RAS activation involves exchanging GDP for GTP, which drives downstream signaling; RAS then inactivates itself by hydrolyzing GTP back to GDP.
    • RAS mutations are very common in cancers.
    • RAS mutations (e.g., Gly to Val at codon 12) are frequent oncogenic drivers, leading to continuous signalling.
    • Mutations in RAF (e.g. V600E) are also common cancer drivers, leading to constitutive kinase activity.

    The PI3K Pathway

    • The PI3K pathway, activated by signals like insulin, triggers a signaling cascade leading to AKT activation.
    • PIP3 generation is critical, and recruits proteins (PDK1 and AKT).
    • Akt activation leads to cell growth, protein synthesis, and apoptosis suppression via downstream targets like mTOR.
    • Turning off the pathway involves signal removal, receptor deactivation, PIP3 dephosphorylation (via PTEN), and AKT dephosphorylation.

    Targeted Treatments

    • Personalized medicine in cancer is beneficial, and aims to target specific signalling pathways in individual tumors based on their genetic characteristics.

    Receptor Tyrosine Kinase and Cancer

    • RTKs can be targeted using inhibitors. Mutations, amplification, and overexpression of RTKs drive cancer development.
      • RTK inhibitors can block ligand binding, dimerisation and kinase activity, leading to tumour cell killing.

    HER2 and Breast Cancer

    • HER2 is a RTK often amplified in breast cancers, leading to constitutive signalling.
    • Antibodies targeting HER2 (like Trastuzumab and Pertuzumab) are used to treat HER2-positive breast cancer.

    BCR-ABL Fusion Kinase

    • In certain cancers, the BCR and ABL genes fuse, forming a constitutively active BCR-ABL fusion kinase.
    • This fusion leads to uncontrolled cell growth and survival, commonly seen in chronic myelogenous leukemia (CML).
    • BCR-ABL inhibitors, like Imatinib (Gleevec), target the activated kinase, effectively treating CML.

    Resistance to Inhibitors

    • Resistance to inhibitors, like Imatinib, emerges through mutations in the cancer cells that impact drug binding or target function, leading to relapse in some cases.

    Studying That Suits You

    Use AI to generate personalized quizzes and flashcards to suit your learning preferences.

    Quiz Team

    Description

    Explore the intricate world of cell signalling and its critical role in cancer. This quiz covers the mechanisms of extrinsic and intrinsic signals, how they interact with receptors, and their impact on cellular behaviour such as proliferation and apoptosis. Test your knowledge on key signalling pathways and their implications in cancer development.

    More Like This

    Use Quizgecko on...
    Browser
    Open
    Browser
    Browser