Topic Cell Signaling

Topic 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

Topic 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

Topic Multiple levels of cell signaling Cell Signaling

Topic 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

Topic Forms of signaling molecules Gasses NO CO Steroid Hormones Testosterone Estradiol Progesterone Glucocorticoids Cortisol Mineralocorticoids Aldosterone Cell Signaling

Topic Forms of signaling molecules Neurotransmitters Cell Signaling

Topic Forms of signaling molecules Peptide Hormones and Growth Factors Cell Signaling

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

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

Topic Cell Signaling The 2 adrenoceptor -S-S- Extracellular domain Intracellular domain Transmembrane domain

Topic 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

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

Topic 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

Topic 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

Topic 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

Topic 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

Topic 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

Topic Cell Signaling The Insulin Receptor Cascades Phosphatidylinositol-3- hydroxy kinase (PI3K)

Topic 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

Topic 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

Topic 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