1. Topic 14-11 14 Cell Signaling

2. Topic 14-12 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 Cell Signaling

3. Topic 14-13 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 Cell Signaling

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

5. Topic 14-15 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 Cell Signaling

6. Topic 14-16 Forms of signaling molecules Gasses NO CO Steroid Hormones Testosterone Estradiol Progesterone Glucocorticoids Cortisol Mineralocorticoids Aldosterone Cell Signaling

7. Topic 14-17 Forms of signaling molecules Neurotransmitters Cell Signaling

8. Topic 14-18 Forms of signaling molecules Peptide Hormones and Growth Factors Cell Signaling

9. Topic 14-19 Forms of receptors Steroid receptors Present in the cytoplasm or localized in the nucleus Recall Glucocorticoid receptor – interaction with the GRE Cell Signaling

10. Topic 14-110 Forms of receptor G protein-coupled receptors Seven transmembrane helix family Progesterone R -adrenoceptors Cell Signaling

11. Topic 14-111 Cell Signaling The 2 adrenoceptor -S-S- Extracellular domain Intracellular domain Transmembrane domain

12. Topic 14-112 Forms of receptors Tyrosine Kinase Receptors Not only a receptor Also an enzyme Tyrosine kinase Examples Insulin R IGF Type 1 R EGF Cell Signaling

13. Topic 14-113 Forms of receptors Cytokine superfamily receptors No catalytic domain Interact with nonreceptor protein- tyrosine kinases Src family JAK family Cell Signaling

14. Topic 14-114 Bla nk Bla nk The Insulin Receptor Cascades IR is a receptor tyrosine kinase A family of receptors involved in cell growth and differentiation Tetramer Two and two subunits Cell Signaling

15. Topic 14-115 Bla nk Bla nk 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) Cell Signaling

16. Topic 14-116 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 Cell Signaling

17. Topic 14-117 The Insulin Receptor Cascades Insulin receptor substrates (IRSs) Insulin may signal along several independent pathways One of these is phosphatidylinositol-3-hydroxy kinase (PI3K) Cell Signaling

18. Topic 14-118 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 (PIP 2 ) 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

19. Topic 14-119 Cell Signaling The Insulin Receptor Cascades Phosphatidylinositol-3- hydroxy kinase (PI3K)

20. Topic 14-120 Cell Signaling The Insulin Receptor Cascades Protein kinase B PIP 2 recruits PKB to plasma membrane Binding – conformational change Transfer of glucose transporters to the plasma membrane Increased protein synthesis Glycogen synthase Glucose to glycogen

21. Topic 14-121 The Insulin Receptor Cascades Insulin receptor substrates (IRSs) Insulin may signal along several independent pathways Another IRS pathway: Ras – cell growth and proliferation Cell Signaling

22. Topic 14-122 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 Cell Signaling