Generalized Signaling Pathway
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Transcript of Generalized Signaling Pathway
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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
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Forms of Cell Signaling
• Paracrine: signal molecule secreted and acts locally• Contact-dependent: signal molecule remains bound
to signaling cell
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• Endocrine: signal molecule secreted into bloodstream
• Synaptic: neurotransmitter acts at synaptic contacts
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• Gap junctions: allow passage of small signaling molecules
• Autocrine: signaling cell signals to cells of the same type and to itself
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Speed of Signaling Response
• Alterations to proteins already present occurs rapidly• New gene expression and protein synthesis occurs slowly
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• Cell responds to set of signals based on its receptors• Signals act in different combinations to effect behavior of
cell
Response to Combinations of Signals
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• Different receptors• Same receptor coupled to different intracellular signaling
machinery
Different Responses to Same Signal
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• Ion-channel-linked: neurotransmitter controls opening of ion channel
• G-protein-linked: intracellular signaling mediated by trimeric GTP-binding protein
Types of Cell Surface Receptors
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• Enzyme-linked: function as enzyme or directly associated with enzyme
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• Chain of molecular interactions between receptor and target protein
• Small intracellular mediators (second messengers)
• Intracellular signaling proteins
Relaying Signal Within Cell
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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
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Induced Interactions of Signaling Proteins
• Intracellular signaling propagated by inducing protein interactions• Interaction domains in signaling proteins• Adaptor proteins
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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
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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
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Target Cell Desensitization
• Decreased response to signal at particular level following prolonged exposure
• Negative feedback with short delay• Signaling machinery modified, less responsive
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Receptor-Mediated Activation of G Proteins
• Trimeric G protein ()• Inactive when GDP bound to • Activation of receptor causes
dissociation of from and exchange of GDP for GTP
• Activated mediates signaling
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Turning off G proteins
• Stimulation of GTPase activity of by interaction with target signaling protein or specific RGS
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• Receptors linked to Gs activate adenylyl cyclase
• Converts ATP to cAMP, which acts a small intracellular mediator• Activates cAMP-dependent protein kinase (PKA)
Signaling by cAMP
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Cholera & Pertussis Toxins
• Gs subunit activates adenylyl cyclase• Cholera toxin: ADP ribosylation of Gs (); cannot
hydrolyze GTP
• Gi subunit inhibits adenylyl cyclase• Pertussis toxin: ADP ribosylation of Gi (); prevents
binding to receptors
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• Receptors linked to Gq activate phospholipase C-• 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)
Signaling by Inositol Phospholipids
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Cleavage by Phospholipase C-
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• G protein-linked receptor kinases phosphorylate activated receptor
• Arrestin binding prevents G protein interaction, promotes endocytosis
Receptor Desensitization
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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
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Calcineurin-NFAT Signaling in T Cells
• Calcineurin dephosphorylates, activates NFAT
• NFAT turns on genes for T cell activation
• Cyclosporin inhibits calcineurin and thereby NFAT
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Signaling Through Enzyme-Linked Receptors
• Ligand binds to extracellular side of receptor• Activates enzyme activity present or
associated with cytoplasmic side
– Receptor tyrosine kinases– Tyrosine kinase associated receptors– Receptor tyrosine phosphatases– Receptor serine/threonine kinases– Receptor guanylyl cyclases
• Classes:
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Receptor Tyrosine Kinases
Examples of RTK subfamilies
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• Ligand-induced receptor dimerization/oligomerization• Cross-phosphorylation of receptors
Activation of Receptor Tyrosine Kinases
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Recruiting Intracellular Signaling Proteins
• Tyrosine phosphorylation generates binding sites for specific signaling proteins
• Most proteins that bind to activated receptor have SH2 domains
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Examples of SH2-Containing Proteins
• Enzymes, for example phospholipase C-γ• Proteins that function as adaptors
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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
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• Chain of three protein kinases that are sequentially activated• Ras activates first kinase in chain
MAP Kinase Pathway
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• 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 Nitric Oxide
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• Ligand-activated gene regulatory proteins• Ligands diffuse through plasma membrane,
include steroid hormones, thyroid hormone, retinoic acid
Signaling by Nuclear Receptors
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Selective Estrogen Receptor Modulators
• Antagonists in some cell types and agonists in others• Tamoxifen as breast cancer therapy• Raloxifene to help prevent osteoporosis