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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 • 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 • Contact-dependent: signal molecule remains bound to signaling cell
Endocrine: signal molecule secreted into bloodstream • Synaptic: neurotransmitter acts at synaptic contacts
Autocrine: signaling cell signals to cells of the same type and to itself • Gap junctions: allow passage of small signaling molecules
Speed of Signaling Response • Alterations to proteins already present occurs rapidly • New gene expression and protein synthesis occurs slowly
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
Different Responses to Same Signal • Different receptors • Same receptor coupled to different intracellular signaling machinery
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
Enzyme-linked: function as enzyme or directly associated with enzyme
Relaying Signal Within Cell • Chain of molecular interactions between receptor and target protein • Small intracellular mediators (second messengers) • Intracellular signaling proteins
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
Induced Interactions of Signaling Proteins • Intracellular signaling propagated by inducing protein interactions • Interaction domains in signaling proteins • Adaptor proteins
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
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
Target Cell Desensitization • Decreased response to signal at particular level following prolonged exposure • Negative feedback with short delay • Signaling machinery modified, less responsive
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
Turning off G proteins • Stimulation of GTPase activity of a by interaction with target signaling protein or specific RGS
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)
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
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)
Receptor Desensitization • G protein-linked receptor kinases phosphorylate activated receptor • Arrestin binding prevents G protein interaction, promotes endocytosis
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
Calcineurin-NFAT Signaling in T Cells • Calcineurin dephosphorylates, activates NFAT • NFAT turns on genes for T cell activation • Cyclosporin inhibits calcineurin and thereby NFAT
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
Receptor Tyrosine Kinases Examples of RTK subfamilies
Activation of Receptor Tyrosine Kinases • Ligand-induced receptor dimerization/oligomerization • Cross-phosphorylation of receptors
Recruiting Intracellular Signaling Proteins • Tyrosine phosphorylation generates binding sites for specific signaling proteins • Most proteins that bind to activated receptor have SH2 domains
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
MAP Kinase Pathway • Chain of three protein kinases that are sequentially activated • Ras activates first kinase in chain
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
Signaling by Nuclear Receptors • Ligand-activated gene regulatory proteins • Ligands diffuse through plasma membrane, include steroid hormones, thyroid hormone, retinoic acid
Selective Estrogen Receptor Modulators • Antagonists in some cell types and agonists in others • Tamoxifen as breast cancer therapy • Raloxifene to help prevent osteoporosis