14 Cell Signaling

1. 14 Cell Signaling Topic 14-1

2. Cell Signaling • Focus on higher order vertebrates • Multiple levels of cell signaling • Endocrine • Cells producing signaling factors are physically separated • Messenger molecules are secreted • Carried in blood or extra-cellular fluid • Target Cells • Membrane receptors • Intracellular actions via signal cascade • Cytoplasmic receptors • Usually a specific transport system to move signal molecule-receptor complex to nucleus – response element Topic 14-1

3. Cell Signaling • Multiple levels of cell signaling • Paracrine • Features most similar to endocrine signaling • Major difference • Target cell found in the same tissue • Messenger molecules carried across extra-cellular matrix or through extra-cellular fluid • Many growth factors are associated with the matrix • Autocrine • Cellular self-signaling Topic 14-1

4. Cell Signaling • Multiple levels of cell signaling Topic 14-1

5. Cell Signaling • Multiple levels of cell signaling • Adhesion • Cell to cell interaction • Cells identify cell-types nearby • Cell to extra-cellular matrix interaction • Cells identify their physical environment Topic 14-1

6. Cell Signaling • Forms of signaling molecules • Gasses • NO • CO • Steroid Hormones • Testosterone • Estradiol • Progesterone • Glucocorticoids • Cortisol • Mineralocorticoids • Aldosterone Topic 14-1

7. Cell Signaling • Forms of signaling molecules • Neurotransmitters Topic 14-1

8. Cell Signaling • Forms of signaling molecules • Peptide Hormones and Growth Factors Topic 14-1

9. Cell Signaling • Forms of receptors • Steroid receptors • Present in the cytoplasm or localized in the nucleus • Recall Glucocorticoid receptor – interaction with the GRE Topic 14-1

10. Cell Signaling • Forms of receptor • G protein-coupled receptors • Seven transmembrane helix family • Progesterone R • b-adrenoceptors Topic 14-1

11. Extracellular domain - S - S - Transmembrane domain Intracellular domain Cell Signaling b The adrenoceptor 2 Topic 14-1

12. Cell Signaling • Forms of receptors • Tyrosine Kinase Receptors • Not only a receptor • Also an enzyme • Tyrosine kinase • Examples • Insulin R • IGF Type 1 R • EGF Topic 14-1

13. Cell Signaling • Forms of receptors • Cytokine superfamily receptors • No catalytic domain • Interact with nonreceptor protein-tyrosine kinases • Src family • JAK family Topic 14-1

14. Bla nk Bla nk Cell Signaling • The Insulin Receptor Cascades • IR is a receptor tyrosine kinase • A family of receptors involved in cell growth and differentiation • Tetramer • Two a and two b subunits Topic 14-1

15. Bla nk Bla nk Cell Signaling • The Insulin Receptor Cascades • Absence of insulin – tyrosine kinanse is inactive • Binding causes a conformational change • Activated tyrosine kinase transfers phosphate groups to: • Specific tyrosines of alternate subunit autophosphorylation • A soluble protein substrate (family) – insulin receptor substrates (IRSs) Topic 14-1

16. Cell Signaling • The Insulin Receptor Cascades • Insulin receptor substrates (IRSs) • Phosphorylated IRS – a single function – to activate downstream messengers • Like several other signaling proteins contains an SH2 domain • SH2 domains have high affinity for phosphorylated tyrosines • Possession of these SH2 modules allows proteins in a signal cascade to be strung together • Different cells contain different protein messengers with SH2 domains • Insulin signaling varies in effect depending on cell type Topic 14-1

17. Cell Signaling • The Insulin Receptor Cascades • Insulin receptor substrates (IRSs) • Insulin may signal along several independent pathways • One of these is phosphatidylinositol-3-hydroxy kinase (PI3K) Topic 14-1

18. Blan k Cell Signaling • The Insulin Receptor Cascades • Phosphatidylinositol-3-hydroxy kinase (PI3K) • Catalyses phosphate addition to the 3’ position on the sugar ring of phosphatidyl inositol • Products: • PI 3,4-biphosphate (PIP2) • PI 3,4,5-triphosphate (PIP3) • Remain in the cytosolic leaflet of lipid bilayer • Membrane-bound lipid messengers • Diverse functions in many cell types • Activation of protein kinase B via its PH domain Topic 14-1

19. Cell Signaling • The Insulin Receptor Cascades • Phosphatidylinositol-3-hydroxy kinase (PI3K) Topic 14-1

20. Cell Signaling • The Insulin Receptor Cascades • Protein kinase B • PIP2 recruits PKB to plasma membrane • Binding – conformational change • Transfer of glucose transporters to the plasma membrane • Increased protein synthesis • Glycogen synthase • Glucose to glycogen Topic 14-1

21. Cell Signaling • The Insulin Receptor Cascades • Insulin receptor substrates (IRSs) • Insulin may signal along several independent pathways • Another IRS pathway: Ras – cell growth and proliferation Topic 14-1

22. Cell Signaling • The Insulin Receptor Cascades • Ras • ras gene - originally discovered as a viral oncogene • Also part of the normal genome • Many tumor cells contain a mutant ras • Protein product Ras • Small G-protein • At inner surface of plasma membrane • Lipid group embedded in inner leaflet Topic 14-1