Chapter 1

1. Chapter 1 Aspects of Cellular Signalling (Signaling)

2. Chapter Objectives • Understand the general principles governing cellular signaling • Good signals • Types of signaling • Amplification of signals • Control of signals • Adaptor molecules

3. Importance • Cells must be able to sense environment • Cells must react to environment • Single celled organisms pass signals • Multicellular organisms have similar signals • Normal state compared to disease state • Rapid growth of the field • March, 2009 – 361,604 hits • Oct, 2013 – 527,279 hits

4. Main Principles • Signal arrives at cell surface • Signal is passed to inside of cell • Signal is propagated inside the cell “cascade” • Message reaches final destination • Cell does a response to signal Nucleus receptor New proteins Cytoplasm organelle

5. Difficulty with Pathways • Pathways are not linear • One signal can activate many pathways • Cells receive more than one signal at a time • How do they integrate? • Amplification of signals is often necessary

6. Good Signals Enzyme • Must have specificity • Small and have rapid diffusion (usually) • Rapidly created • From a common source (ATP?) • Sequestered for later use • Can be turned off quickly Cell Enzyme Cell

7. Types of Cell Signaling • Electrical – synaptic • Endocrine • Paracrine • Autocrine • Cell-Cell • Receptor-ligand • Gap Junctions

8. Electrical Signals Synapses – receive signals from other cells Axon terminal – sends signals to next cell

9. Endo/para/auto-crine signaling • Endocrine – signal from one cell effect a cell far away • Paracrine – signal from one cell effect a cell nearby • Autocrine – signal from one cell effect itself Signaling cell Target cell Non-Target cell Target cell

10. Receptor Ligand Signaling • One cell has receptor – one cell has ligand In flies … receptor ligand RTK Sevenless Sev Bride of sevenless Boss Second messenger Son of sevenless Sos

11. Gap Junctions Many isoforms of connexin Gaps size is dictated by connexin isoform Allows approximately <1200 Da chemicals through

12. Signal Amplification Second messenger Second messenger Phosphorylation Phosphorylation Phosphorylation Second messenger Phosphorylation Phosphorylation Phosphorylation Phosphorylation Phosphorylation Phosphorylation Kinase Kinase Kinase Active enzymes Active enzymes Active enzymes Active enzymes Active enzymes Active enzymes Active enzymes Active enzymes Active enzymes Lots of Product!!

13. Coordination of Signals Receptor 1 Receptor 2 Receptor A B G A B C D H C E Effect K Effect F Effect Effect

14. Scaffolding Proteins? • Why is there no long range signal amplification in cells? Diffusion?

15. Domains • Catalytic • Regulatory • Specific Function • EF-hand • Ca2+ binding • SH2 and SH3 • Protein/protein • PH (Pleckstrin homology) • Protein/protein • 14-3-3 • Protein/protein • Regulation

16. Oncogenes • Genes that lead to cancer • Many are cell signaling molecules • Four Classes • Class 1 • Platlet growth factors • Class 2 • Epidermal and nerve growth factors • Class 3 • Cytosolic kinases • Class 4 • Nuclear transcription factors