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Chapter 5: Growth Factors, Receptors, and Cancer PowerPoint Presentation
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Chapter 5: Growth Factors, Receptors, and Cancer

Chapter 5: Growth Factors, Receptors, and Cancer

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Chapter 5: Growth Factors, Receptors, and Cancer

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Presentation Transcript

  1. Chapter 5: Growth Factors, Receptors, and Cancer

  2. Spatial and temporal control of cell growth and differentiation via communication between individual cells are pivotal for maintaining functional and structural integrity of tissues and organs

  3. e.g. Wound healing

  4. Effect of growth factors on cell proliferation and migration

  5. Experimental clues for cell-to-cell signaling via growth factors from studies for the tyrosine kinase activity of v-Src

  6. Pleiotropic actions and substrate specificity of protein kinases

  7. [1] Receptor tyrosine kinases (RTKs)

  8. Structures of RTKs

  9. Alterations in structures and expression of RTKs make them function as oncogenes

  10. Transphosphorylation underlies the operation of RTKs Human A431 epidermoid carcinoma cells

  11. 206 human glioblastomas

  12. Alternative mechanisms of growth factor-induced receptor dimerization

  13. Constitutive dimerization of RTKs by gene fusion

  14. Multiple structural alteration affecting Kit firing

  15. [2] Cytokine receptor noncovalently interacting with tyrosine kinases

  16. [3] Receptors with serine/threonine kinase activity

  17. [4] Notch receptor of which activation depends on proteolytic cleavage

  18. [5] Patched-smoothened signaling system (Hedgehog pathway)

  19. [6] Canonical Wnt signalingvia frizzled receptors

  20. [6] Non-canonical Wnt signalingvia frizzled receptors: G-protein-coupled receptor (GPCR)

  21. [7] Nuclear receptors activated by lipophilic ligands

  22. [8] Receptors sensing association between the cell and the extracellular matrix (ECM)

  23. Integrins

  24. Integrin tethering to the ECM and cytoskeleton

  25. Suppressed mammary tumorigenesis in the absence of b1 integrin

  26. Activation of Ras, a small-GTP binding protein, by RTKs

  27. EGFR overexpression:  Colorectal cancer (22-77%)  Pancreatic cancer (30-50%)  Lung cancer (40-80%)  Non-small cell lung cancer (14-91%) Ras mutation:  Papillary thyroid cancer (90%)  Pancreatic cancer (60%)  Colon cancer (50%)  Non-small cell lung cancer (30%) SOS Ras* EGFR* EGFR* Grb2 Imatinib Farnesyl transferase B-raf mutation:  Melanoma (70%)  Papillary thyroid cancer (50%)  Colon cancer (10%) Raf* SB590885 PLX4720 XL281 RAF256 Sorafenib PLX4032 EGFR mutaion:  NSCLC (10%)  Glioblastoma (20%) MEK XL518 CI-1040 PD035091 AZD6244 GSK1120212 ERK1/2 Myc RSK Elk-1 Transcription Translation Survival / Proliferation / Suppression of apoptosis Ras/Raf/MAPK signaling cascade activated in human cancers and anti-cancer drugs, targeting the pathway, currently in development. Asterisk indicates mutations found in human cancers.

  28. Alternative mechanisms of transformation by Ras