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Generalized Signaling Pathway

Generalized Signaling Pathway. Release signal molecule from signaling cell Bind and activate receptor in target cell Activate intracellular signaling pathway Alter effector protein(s) to change cell behavior. Forms of Cell Signaling. Paracrine: signal molecule secreted and acts locally

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Generalized Signaling Pathway

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  1. Generalized Signaling Pathway • Release signal molecule from signaling cell • Bind and activate receptor in target cell • Activate intracellular signaling pathway • Alter effector protein(s) to change cell behavior

  2. Forms of Cell Signaling • Paracrine: signal molecule secreted and acts locally • Contact-dependent: signal molecule remains bound to signaling cell

  3. Endocrine: signal molecule secreted into bloodstream • Synaptic: neurotransmitter acts at synaptic contacts

  4. Autocrine: signaling cell signals to cells of the same type and to itself • Gap junctions: allow passage of small signaling molecules

  5. Speed of Signaling Response • Alterations to proteins already present occurs rapidly • New gene expression and protein synthesis occurs slowly

  6. Response to Combinations of Signals • Cell responds to set of signals based on its receptors • Signals act in different combinations to effect behavior of cell

  7. Different Responses to Same Signal • Different receptors • Same receptor coupled to different intracellular signaling machinery

  8. Types of Cell Surface Receptors • Ion-channel-linked: neurotransmitter controls opening of ion channel • G-protein-linked: intracellular signaling mediated by trimeric GTP-binding protein

  9. Enzyme-linked: function as enzyme or directly associated with enzyme

  10. Relaying Signal Within Cell • Chain of molecular interactions between receptor and target protein • Small intracellular mediators (second messengers) • Intracellular signaling proteins

  11. Some Ways for Intracellular Signaling Proteins to Relay Signal • Generate small intracellular mediators • Induced to interact with other signaling proteins • Act as molecular switches • Phosphorylation and de-phosphorylation • GTP binding and hydrolysis • Other mechanisms

  12. Induced Interactions of Signaling Proteins • Intracellular signaling propagated by inducing protein interactions • Interaction domains in signaling proteins • Adaptor proteins

  13. Molecular Switches Regulated by Phosphorylation • Covalent attachment of phosphate by kinases, removal by phosphatases • Different signaling proteins can be activated by phosphorylation or de-phosphorylation

  14. Molecular Switches Regulated by GTP Binding • Active when GTP-bound; inactive when GDP-bound • GTP binding by guanine nucleotide exchange factors, hydrolysis by GTPase activating proteins

  15. Target Cell Desensitization • Decreased response to signal at particular level following prolonged exposure • Negative feedback with short delay • Signaling machinery modified, less responsive

  16. Receptor-Mediated Activation of G Proteins • Trimeric G protein (abg) • Inactive when GDP bound to a • Activation of receptor causes dissociation of a from bg and exchange of GDP for GTP • Activated a mediates signaling

  17. Turning off G proteins • Stimulation of GTPase activity of a by interaction with target signaling protein or specific RGS

  18. Signaling by cAMP • Receptors linked to Gs activate adenylyl cyclase • Converts ATP to cAMP, which acts a small intracellular mediator • Activates cAMP-dependent protein kinase (PKA)

  19. Cholera & Pertussis Toxins • Gsa subunit activates adenylyl cyclase • Cholera toxin: ADP ribosylation of Gs (a); cannot hydrolyze GTP • Gia subunit inhibits adenylyl cyclase • Pertussis toxin: ADP ribosylation of Gi (a); prevents binding to receptors

  20. Signaling by Inositol Phospholipids • Receptors linked to Gq activate phospholipase C-b • PI(4,5)P2 cleaved to diacylglycerol and IP3 • IP3 opens channels in ER causing influx of Ca2+ into cytosol • Diacylglycerol activates protein kinase C (PKC)

  21. Cleavage by Phospholipase C-b

  22. Receptor Desensitization • G protein-linked receptor kinases phosphorylate activated receptor • Arrestin binding prevents G protein interaction, promotes endocytosis

  23. Ca2+ as Small Intracellular Mediator • Involved in PKC activation • Binds calmodulin to regulate other proteins • Activates CaM-kinases • Activates calcineurin, a phosphatase, whose substrates include NFAT

  24. Calcineurin-NFAT Signaling in T Cells • Calcineurin dephosphorylates, activates NFAT • NFAT turns on genes for T cell activation • Cyclosporin inhibits calcineurin and thereby NFAT

  25. Signaling Through Enzyme-Linked Receptors • Ligand binds to extracellular side of receptor • Activates enzyme activity present or associated with cytoplasmic side • Classes: • Receptor tyrosine kinases • Tyrosine kinase associated receptors • Receptor tyrosine phosphatases • Receptor serine/threonine kinases • Receptor guanylyl cyclases

  26. Receptor Tyrosine Kinases Examples of RTK subfamilies

  27. Activation of Receptor Tyrosine Kinases • Ligand-induced receptor dimerization/oligomerization • Cross-phosphorylation of receptors

  28. Recruiting Intracellular Signaling Proteins • Tyrosine phosphorylation generates binding sites for specific signaling proteins • Most proteins that bind to activated receptor have SH2 domains

  29. Receptor-Mediated Activation of Ras • Ras is monomeric GTP binding protein • Grb-2 adaptor has SH2 domain that binds activated receptor • Grb-2 also binds Ras GEF, which activates Ras

  30. MAP Kinase Pathway • Chain of three protein kinases that are sequentially activated • Ras activates first kinase in chain

  31. Signaling by Nitric Oxide • Diffuses across plasma membrane from signaling cell into target cell • NO activates guanylyl cyclase in smooth muscle to cause relaxation • Viagra inhibits cGMP phosphodiesterase

  32. Signaling by Nuclear Receptors • Ligand-activated gene regulatory proteins • Ligands diffuse through plasma membrane, include steroid hormones, thyroid hormone, retinoic acid

  33. Selective Estrogen Receptor Modulators • Antagonists in some cell types and agonists in others • Tamoxifen as breast cancer therapy • Raloxifene to help prevent osteoporosis

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