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

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

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

Signal N M S G2G1 ECM Y Y apoptosis Survival

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

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

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

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

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

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

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

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.

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

SH2

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

SH2 P inactive active

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

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