1. 02.08.10 Lecture 10: Cell Communication II

2. GPCR signaling is inactivated by arrestins

3. Calcium transients trigger many cellular processes Many signals trigger Ca +2 release (not just GPCRs) Skeletal muscle contracts in response to calcium release Ca +2 triggers regulated secretion (I.e. in neurons) Sperm entry triggers a calcium wave during fertilization

4. Fertilization induces a rise in Ca +2 that starts embryogenesis Starfish egg loaded with a calcium-sensitive fluorescent dye Fertilized in vitro and monitored by fluorescence microscopy

5. Fertilization induces a rise in Ca +2 that starts embryogenesis

6. The effects of calcium in the cytosol are mediated by calcium-binding proteins Protein kinase C: activated by calcium & DAG Calmodulin: activated by conformational change by calcium binding Ca +2 /calmodulin-dependent kinase (Cam-kinase): activated by Ca +2 -calmodulin

7. Activation of CaM-kinase

8. 3 classes of cell surface receptors

9. Enzyme-linked receptors fall into 3 categories 1. Receptor tyrosine kinases 2. Cytokine receptors 3. TGF-  receptors

10. 1. Receptor tyrosine kinases Ligands are soluble or membrane-bound peptide or protein hormones (I.e. insulin, growth factors) Some RTKs have been identified in studies of human cancers - mutant forms send proliferative signals to cells in absence of signal

11. Receptor tyrosine kinases autophosporylate themselves Phosphorylate tyrosine residues on target proteins and on themselves Activation of a receptor tyrosine kinase stimulates assembly of a signaling complex

12. Tyrosine receptor signaling complexes As many as 10 or 20 downstream signaling molecules - differ between receptors Components such as phospholipases, lipid kinases, other protein kinases, and Ras Complexes are disassembled by protein tyrosine phosphatases

13. Receptor tyrosine kinases activate the G protein Ras

14. GTP binding to Ras induces a conformational change

15. Ras activates a cascade of kinases called MAP-kinases Scaffolding protein

16. RTKs can activate the PI-3-kinase-Akt pathway

17. Activated Akt serves as a survival signal for the cell and stimulates cell growth

18. 2. Cytokine receptors Cytokines are small secreted proteins Control growth and differentiation of many types of tissues (I.e. induce formation of different types of blood cells, interferons)

19. Cytokine receptors signal to the nucleus in a direct pathway

20. 3. TGF  receptor signaling TGF  - transforming growth factor  A number of related extracellular signaling molecules important during development Exert anti-proliferative signals to cells - loss of function can contribute to malignancy Mutations in this pathway are often associated with pancreatic cancers but also implicated in colon, liver, and gastric tumors

21. TGF-  receptors activate gene regulatory proteins at the membrane

22. Signaling pathways exhibit a high degree of interconnectedness

23. Some signaling proteins act to integrate incoming signals

24. Receptor signaling may be inactivated via different mechanisms