L4 Cell Signalling

• Proteasome inhibitor to treat multiple myeloma

  Bortezomib - more patients without progression over time
• Where does Bortezomib bind to in 26S proteasome?

  Chymotrypsin-like subunit of the 26S proteasome
• What is the 'Archilles' heel' for multiple myeloma (BM cancer)?

  Proteasome activity
• What is multiple myeloma highly dependent on?

  Proteasome activity to clear out 'garbage proteins' for survival
• A treatment for multiple myeloma

  Proteasome inhibitors
• Disadvantage of proteasome inhibitors

  Significant side effects
• A symptom of multiple myeloma

  Brittle bone disease: Bone degeneration with foci formation
• How does a myeloma skull look like?

  Has lytic lesions (punched out lesions) of various sizes
• What is required to overcome resistance to drugs in cancers?

  Combinatorial therapy
• What does dabarafenib target?

  Braf V600E
• What does trametinib target?

  MEK (kinase activity)
• Drug that target MEK

  Trametinib
• Drug that target EGFR

  Osimertinib / Gefitinib
• Why can't the extracellular receptors be targeted only?

  Different receptors can drive the same pathway; Have to prevent resistance
• What is mutated in ~ 50% of malignant melanomas?

  Braf
• Most common mutation of BRAF


  V600E
• RAS/MAPK pathway - signalling cascade

  RAS > RAF > MEK > ERK
• Drugs that target BRAF (2)

  1. Dabrafenib
  2. Vemurafenib
• Where are the mutations found in NSCLC?

  Tyrosine kinase domain (TK)
• Where are the mutations found in CRC?

  Extracellular region - Domain III
• How do lytic lesions form in a myeloma skull? (2)

  1. Osteoclasts - chewed up bone (regulates bone density)
  2. Osteoclasts are overactivated by chemokines, cytokines from hyperactivated B-cells
• Side effects of Bortezomib (2)

  1. Gastro-intestinal effects
  2. Weakness
• Why is multiple myeloma difficult to treat? (2)

  1. Propensity for multiple relapses, cumulative and emergent toxicities
  2. Increasing genomic complexity that arises due to clonal evolution
• Combination of drug used to target malignant melanoma (2)

  1. Dabrafenib
  2. Trametinib
• Signal transduction pathway 

  Ligand > receptor > signal relay > target amplification
• Examples of ligands (signalling molecules) (9)

  1. Hormones
  2. Growth factors
  3. Interleukins
  4. Cytokines
  5. Interferons
  6. Chemokines
  7. Extracellular matrix proteins
  8. Toxins
  9. Neurotransmitters
• Modes of cell signalling (4)

  1. Endocrine - hormones (bloodstream)
  2. Paracrine
  3. Autocrine
  4. Cell-cell contact - eg. Notch signalling
• Receptors involved in RTK signalling (2)

  1. EGFR
  2. TGFB receptors
• Examples of transmembrane receptors (7)

  1. G protein-coupled receptors
  2. Cytokine receptors
  3. Receptor tyrosine kinases (RTKs)
  4. TGFB receptors
  5. Hedgehog (Hh) receptors
  6. Wnt receptors
  7. Notch receptors
• PTM involved in signal transduction (9)

  1. Phosphorylation
  2. Ubiquitylation
  3. SUMOylation
  4. Glycosylation
  5. Methylation
  6. Acetylation
  7. Myristoylation
  8. Farnesylation
  9. Geranylgernylation
• How does phosphorylation affect steric effect of serine/threonine & tyrosine?

  Increases size & MW by about 80 Da; makes them larger & bulkier
• How does phosphorylation affect electric charge of serine/threonine & tyrosine?

  Phosphate group - up to 2 negative charges
• How does phosphorylation affect hydrophobicity of serine/threonine & tyrosine?

  Decrease hydrophobicity
• What do serine, threonine and tyrosine residues have in common?

  Hydroxyl -OH groups
• Amino acid residues for phosphorylation (3)

  1. Serine
  2. Threonine
  3. Tyrosine
• Properties of serine/threonine and tyrosine amino acid residue (3)

  1. Polar
  2. Neutral
  3. Hydrophilic
• Structure of EGFR (5)

  1. Extracellular domain (Domains I, II, III, IV)
  2. Transmembrane domain
  3. Intracellular juxtamembrane domain (iJM)
  4. Tyrosine kinase domain (TK)
  5. Cytoplasmic carboxy tail
• Cancers related to mutations in EGFRs (3)

  1. Glioblastoma - brain
  2. Non-small cell lung cancer (NSCLC) - lung
  3. Colorectal cancer (CRC) - colon
• Where are the mutations found in glioblastoma? (2)

  1. Extracellular region - Domain I - II
  2. Extracellular region - Domain IV
• How does EGF binding to EGFR promote receptor dimerisation then activation? (4)

  1. EGF ligand binds to EGFR leads to structual rearrangements 
  2. This leads to allosteric activation of kinase 
  3. and trans-autophosphorylation of tyrosine residues in the cytoplasmic receptor tail
  4. Trigger the signalling cascade