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Signal Transduction Mechanisms Underlying Growth Control and Oncogenesis

Signal Transduction Mechanisms Underlying Growth Control and Oncogenesis Ronit Sagi-Eisenberg Dept. of Cell and Developmental Biology Sackler School of Medicine Tel Aviv University. M. G2. G1. S.

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Signal Transduction Mechanisms Underlying Growth Control and Oncogenesis

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  1. Signal Transduction Mechanisms Underlying Growth Control and Oncogenesis Ronit Sagi-Eisenberg Dept. of Cell and Developmental Biology Sackler School of Medicine Tel Aviv University

  2. M G2 G1 S Normal tissue function strictly depends on signals for Proliferation and Survival N N

  3. interphase START Signal Cell Cycle Control Exit M M Enter M mitosis G2 checkpoint: cell size environment DNA replicated G1 G2 controler G1checkpoint: cell size environment S

  4. Signal Y M Y apoptosis G2 G1 S ECM Survival N

  5. serine, threonine and tyrosine are subjected to phosphorylation on their free hydroxyl groups. Concept: change in structure leads to a change in function Protein phosphorylation: The most common post-translational modification that regulates biological processes

  6. kinases AA-OHAA-OP phosphatases Protein phosphorylation: The most common post-translational modification that regulates biological processes

  7. Control of cell growth and survival 85% of total protein phosphorylation reactions take place onSer 15% on Thr residues < 0.01% on Tyrresidues.

  8. Signal Y Tyr Tyr-P N M Y apoptosis G2 G1 S ECM

  9. Receptors involved in growth promoting signaling: • Receptor tyrosine kinases- RTKs EGFR; PDGFR; kit… (ii)Tyrosine kinase associated receptors- • Cytokine receptors:Interferons; Interleukins; Tumor necrosis factor (TNF); Colony stimulating factors; Erythropoietin;Growth hormone; Prolactin • Integrins: ECM receptors • Immunological receptors: TCR, FceRI

  10. Monomer- Inactive tyrosine kinase Dimer- Active tyrosine kinase Ligand-dependent dimer- Active kinase

  11. Phosphorylationof the receptor . • Phosphorylationof target proteins.

  12. Phosphorylationof the receptor . • Phosphorylationof target proteins. Phosphorylation of key tyrosines in the receptor creates“docking sites” for cytoplasmic proteins which contain special domains, that allow them to dock onto these phosphorylated tyrosines.

  13. Src kinase Src Homology domain 2 SH2 A typical SH2 domain is composed of 100 amino acids. SH2 domains bind to specific phosphotyrosines (p-Tyr) on the target protein.

  14. SH2 SH2

  15. SH2 containing proteins: Src kinase Enzymes whose activity is modulated upon binding to the receptor.

  16. P SH2 SH2 inactive active

  17. SH2 containing proteins: Enzymes whose activity is modulated upon binding to the receptor. ii) Adaptor proteins

  18. Signal Y Tyr Tyr-P N M Y apoptosis G2 G1 S ECM

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