Chapter 4 Notes

• Dr. Michael Olson: 'Cell Signalling in Cancer II'
• Week 4:Lecture 1
• Sources: Robert Weinberg: The Biology of Cancer – Chapter 6
• Signal Transduction Pathway


  Definition: Reception, Transduction, Response
• Signal Transduction Pathway - Reception

  Ligand proteins and their activation in cancer
• Signal Transduction Pathway - Reception

  Receptor proteins and their activation in cancer
• Signal Transduction Pathway - Transduction

  Signal transducer proteins and their activation in cancer
• Signal Transduction Pathway - Response


  Response proteins and their activation in cancer
• Putting it all together

  • Examples of signaling pathways in cancer
• Putting it all together

  • KEGG pathway activity
• Transduction - transducer proteins


  • Example: G-proteins
• 1. proteins promote the exchange of GDP by releasing it (Intrinsic Factor) and inactivate Dipage activity; Ras is always on as a result of signal emitting configuration
• The structure of the Ras protein and its response to GTP binding: Gly 12 is closely positioned to γ-PO4, GTP is converted into GDP by removing γ-PO4, mutations in Gly 12 prevent this reaction, KRAS always bound to GTP
• Upstream Ras signaling


  RAS protein is bound to the inner site of the plasma membrane
• How does phosphorylated (activated) RTK transmit signals to RAS protein?

  Concentrates the protein to where it needs to be activated (this is why it needs to be in the plasma membrane)
• Autocrine signalling
• Adaptor proteins link other proteins together and facilitate creation of larger signaling complexes (bridge proteins). They mediate very specific protein-protein interactions
• Some adaptor proteins have enzymatic activity and don't just bind to anything. Example: adaptor protein Grb2
• Sos induces the release of GDPs and then promotes the binding to GTD, resulting in the activation of the Ras protein. It has 3 domains that fold into this complex and recognizes and looks for proteins with phosphotyrosines
• Adaptor proteins have flanking amino acid residues that determine the specificity of binding to phosphotyrosine. Src homology 2 (SH2) domain is bound to the TK receptor
• SH3 domain binds specifically to certain proline-rich sequence domains in partner proteins
• Receptor phosphotyrosines are homing sites for various SH2 containing proteins
• Each receptor activates a different set of downstream signaling pathways. Single activated receptor can elicit diverse downstream signaling cascades
• Downstream Ras signaling: Activated G12V mutant RAS interacts with multiple downstream effector proteins: PI3K, Raf, and Ral-GEF
• RAS binding to GTP results in switching of its domains enabling an effector loop to interact with multiple downstream effector proteins
• Ras effector pathways include RAS-RAF-MAP Kinase Pathway, PI3 Kinase Pathway, and Ral-GEF Pathway
• Switching


  Enables an effector
• 1004 (Ras Effectors Interphase of as binding to the effector proteins tightly)
• Ras effector pathways at glance

  1. RAS-RAF-MAP Kinase Pathway

  2. PI3 Kinase Pathway

  3. Ral-GEF Pathway
• Signalling Cascades


  • RAS-RAF-MAP Kinase Pathway
  • Receptor-tyrosine Kinase signalling (e.g. ras pathway)
  • Mitogen-activated protein kinase pathway – ligand dependent
  • Mitogen-activated protein kinase pathway – ligand dependent
  • Mitogen-activated protein kinase pathway – ligand independent
  • Mitogen-activated protein kinase pathway – ligand independent
• RAS-RAF-MAP Kinase Pathway


  • Key pathway downstream of Ras
• Once Ras is in its active form


  The affinity of Ras for Raf increases
• Once RAF is activated

  Before this association, Raf begins to phosphorylate MEK (Second Kinase)
• MEK is dual specific


  Will phosphorylate substrates, which in turn will regulate various cellular processes
• AKT/PKB phosphorylates a series of substrates that have multiple effects on the cell

  Include aiding in cell survival by inhibiting apoptosis, stimulating cell proliferation, stimulating cell growth
• The inositol ring of the phospholipids
• If you draw out all the contents towards the edge of the balloon, the contents become more concentrated along this plane
• PTEN removes the phosphate at the 3' region
• Once a cell encounters a mitogen, PIP3 levels increase rapidly
• The removal of phosphate by PTEN suggests 2 distinct mechanisms by which the Akt/PKb pathway can be deregulated in Cancer cells