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

2. N M S G2G1 Normal tissue function strictly depends on signals for Proliferation and Survival Proliferation and Survival N

3. S M G2G2 G1G1 Enter M Exit M START Cell Cycle Control G 1 checkpoint: cell size environment G 2 checkpoint: cell size environment DNA replicated Signal

4. Signal N M S G2G1 ECM Y Y apoptosis Survival

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

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

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

8. Signal M S G2G1 apoptosis N Y ECM Y Tyr Tyr-P

9. Receptors involved in growth promoting signaling: (i)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, Fc  RI

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

12. Phosphorylation  Phosphorylation of the receptor.  Phosphorylation  Phosphorylation of target proteins.

14. Phosphorylation  Phosphorylation of the receptor.  Phosphorylation  Phosphorylation of 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.

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

16. SH2

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

18. SH2 P inactive active

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

20. Signal M S G2G1 apoptosis N Y ECM Y Tyr Tyr-P