Overview of Cancer signalings(tmp)

Overview of Cancer signalings(tmp)：pRb A molecular checkpoint for the cell cycle restriction point；It also contains a design of positive feed back loop。

Overview of Cancer signalings(tmp)

• 7 main families of mammalian cell surface receptors
  • 1. GPCR
    • The downstream signalings of GPCR
      • You can see phospholopase C-β can be activated by both Gq and βγ
  • 2. Cytokine receptors
  • 3. RTK
  • 4. TGFβ receptors
  • 5. Hedgehog(Hh) receptors
  • 6. Wnt receptors
  • 7. Notch receptor
  • Diagram
• Functional modules of cellular signaling circuits
  • Motility Circuits
    • Cell adhersion receptors(receptors that are physically attched with extracellular matrix components)
      • Integrins
        • hetero dimeric structural organization
          • α plus β subunit。
        • Outside in signaling
          • When ectodomains bind to specific components in EM, intermediary proteins will link the cytoplasmic domain of beta subunit to the cytoskeleton(actin fibires). at the same time, the cytoplasmic domains of beta subunit can attract variaty of signaling molecules.
          • The signaling adaptors of integrins
            • FAK(focal adhesion kinase)
              • It can activates most pathways activated by growth factor receptors.
        • inside out signaling
          • cytoplasmic signals can control the binding affinities of integrins for their ECM ligands.
          • this may lead to the breaking existing contacts and forging new ones in their place.
        • roles in cell motility
          • inside out signalings induce integrin to forge new linkages with the ECM.
          • When cell needs to loosen its tehers at the front, signalings will cause release contact with the substratum.
      • E-cadherin
        • Intermediate proteins link cadherin's intracellular domain with cytoskeleton(actin filament).
          • 3 Intermediate proteins are involved, their spacial interactions are indicated above.
            • p120
            • β-catenin
              • The accumulation of β-catenin is very common in cancer.
              • It may promotes cell proliferation by its transcriptional factor activity.
              • How it is regulated
                • axin -> GSK-3β(glycogen synthase kinase-3β) +p-|(targets it for degredation) β-catenin
                  • Apc (Adenomatous polyposis coli) here is part of the protein complex: {axin][GSK-3β][APC][β-catenin][Wtx}
                  • it is critical for the successfuly capture of β-catenin, that is then phosphorylated and targeted to degredation by β-catenin.
                • Wnt -> Frizzled -> Dishevelled - axin -| inactive SK-3β ---|-> β-catenin
                  • this finally promotes cell prolifereation
              • Onco-proteins in and around β-catenin
                • Constitutively activated β-catenin.
                • APC mtants(fail to bind and down regulates β-catenin levels).
            • α-catenin
  • Proliferation Circuits
    • growth factors, RTK and Ras
  • Viability Circuits
    • Bcl2
    • cytokines
    • survival factors
    • deathfactors
  • Cytostasis and Differentiation Circuits
    • tumour suppressor/onco proteins around cell cycle regulations
      • pRb
        • pRb A molecular checkpoint for the cell cycle restriction point
          • pRb -| E2F -o-> Proteins to path restriction points
        • It is phosphorylated by CDKs
          • Cyclin D-CDK4/6 +p pRb -|-> E2F -o-> DNA polymerase and other proteins for DNA synthesis
            • interpretation: pRb is the checkpoint to certain stage of cell cycle, because it normally inhibits cell cycle, and it needs to be induced by CDK2-CyclinE.
        • It also contains a design of positive feed back loop
          • E2F -o-> Clyclin E, CDK-2, E2F
          • CyclinE-CDK-2 +p pRb -|-> E2F -o-> ~~~~
            • So we call it a positive feed back loop
            • The phosphorylation of pRb becomes CyclinD independent.
        • Pictures
        • in cancer, pRb is often inactivated by lose of function mutations.
      • TGFβ
        • TGFβ is the receptor for antigrowth signals, TGFβ activation inhibits the cell cycle progression
        • Type I TGFβ signaling
          • TGFβ -> SMADs --o-> p15, p21
            • p15 -| CyclinD-CDK4-6 --> path of restriction point
            • p21 -| CyclinE-CDK2 --> path of restriction point
          • TGFβ -> SMAD --| Myc-Miz --> p15, p21
            • Myc-Miz -o-| p15ink4b, p21zip -| p15, p21
        • Type II TGFβ signaling
        • in cancer, TGFβ is often inactibated by lose of function mutations.
        • SMADs(the protein adaptors at down stream of TGFβ) is often inactivated by lose of function mutations.
          • smad2- in colon cancer
          • smad4- in pancrease cancer
      • c-Myc
        • cMyc is another cell cycle check point protein, it is a transcroptional factor that can either inhibits or activates cell cycle progression depends on its interacting partners
        • c-Myc can dimerizes with
          • c-Myc(form homodimer)
          • Max
            • Myc-Max is a transcriptional activator
            • Myc-Max -o-> Cyclin D2, E2F1, 2,3 , CDK4
              • results: cell will path G1 checkpoint
          • Miz
            • Myc-Miz can be thought as a transcriptional repressor
              • Miz is a transcriptional activator, and Myc binds and inhibits Miz.
              • Myc -| Miz -o-> p15ink4b, p21zip
            • Myc-Miz -o-| p15ink4b, p21zip -| p15, p21
              • results: cell will not path restriction point
    • anti-growth factors.
    • signals around Cyclin D1
      • Actually all the four modules can finally converge at cyclin D1.
  • Diagram
    • Ps. The regulation through gene expressions would not be completely express or completely not, they only some extend up or down regulates the gene product, so the oncogenicities depend on the lose of balance between a positive regulation hubnodes(such as MYC) and negative regulation hubnodes(such as TGF-β）.