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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

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. Forms of Cell Signaling. Paracrine: signal molecule secreted and acts locally - PowerPoint PPT Presentation

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Page 1: 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

Page 2: Generalized Signaling Pathway

Forms of Cell Signaling

• Paracrine: signal molecule secreted and acts locally• Contact-dependent: signal molecule remains bound

to signaling cell

Page 3: Generalized Signaling Pathway

• Endocrine: signal molecule secreted into bloodstream

• Synaptic: neurotransmitter acts at synaptic contacts

Page 4: Generalized Signaling Pathway

• Gap junctions: allow passage of small signaling molecules

• Autocrine: signaling cell signals to cells of the same type and to itself

Page 5: Generalized Signaling Pathway

Speed of Signaling Response

• Alterations to proteins already present occurs rapidly• New gene expression and protein synthesis occurs slowly

Page 6: Generalized Signaling Pathway

• 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

Page 7: Generalized Signaling Pathway

• Different receptors• Same receptor coupled to different intracellular signaling

machinery

Different Responses to Same Signal

Page 8: Generalized Signaling Pathway

• 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

Page 10: Generalized Signaling Pathway

• Chain of molecular interactions between receptor and target protein

• Small intracellular mediators (second messengers)

• Intracellular signaling proteins

Relaying Signal Within Cell

Page 11: Generalized Signaling Pathway

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

Page 12: Generalized Signaling Pathway

Induced Interactions of Signaling Proteins

• Intracellular signaling propagated by inducing protein interactions• Interaction domains in signaling proteins• Adaptor proteins

Page 13: Generalized Signaling Pathway

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

Page 14: Generalized Signaling Pathway

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

Page 15: Generalized Signaling Pathway

Target Cell Desensitization

• Decreased response to signal at particular level following prolonged exposure

• Negative feedback with short delay• Signaling machinery modified, less responsive

Page 16: Generalized Signaling Pathway

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

Page 17: Generalized Signaling Pathway

Turning off G proteins

• Stimulation of GTPase activity of by interaction with target signaling protein or specific RGS

Page 18: Generalized Signaling Pathway

• 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

Page 19: Generalized Signaling Pathway

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

Page 20: Generalized Signaling Pathway

• 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

Page 21: Generalized Signaling Pathway

Cleavage by Phospholipase C-

Page 22: Generalized Signaling Pathway

• G protein-linked receptor kinases phosphorylate activated receptor

• Arrestin binding prevents G protein interaction, promotes endocytosis

Receptor Desensitization

Page 23: Generalized Signaling Pathway

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

Page 24: Generalized Signaling Pathway

Calcineurin-NFAT Signaling in T Cells

• Calcineurin dephosphorylates, activates NFAT

• NFAT turns on genes for T cell activation

• Cyclosporin inhibits calcineurin and thereby NFAT

Page 25: Generalized Signaling Pathway

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:

Page 26: Generalized Signaling Pathway

Receptor Tyrosine Kinases

Examples of RTK subfamilies

Page 27: Generalized Signaling Pathway

• Ligand-induced receptor dimerization/oligomerization• Cross-phosphorylation of receptors

Activation of Receptor Tyrosine Kinases

Page 28: Generalized Signaling Pathway

Recruiting Intracellular Signaling Proteins

• Tyrosine phosphorylation generates binding sites for specific signaling proteins

• Most proteins that bind to activated receptor have SH2 domains

Page 29: Generalized Signaling Pathway

Examples of SH2-Containing Proteins

• Enzymes, for example phospholipase C-γ• Proteins that function as adaptors

Page 30: Generalized Signaling Pathway

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

Page 31: Generalized Signaling Pathway

• Chain of three protein kinases that are sequentially activated• Ras activates first kinase in chain

MAP Kinase Pathway

Page 32: Generalized Signaling Pathway

• 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

Page 33: Generalized Signaling Pathway

• Ligand-activated gene regulatory proteins• Ligands diffuse through plasma membrane,

include steroid hormones, thyroid hormone, retinoic acid

Signaling by Nuclear Receptors

Page 34: Generalized Signaling Pathway

Selective Estrogen Receptor Modulators

• Antagonists in some cell types and agonists in others• Tamoxifen as breast cancer therapy• Raloxifene to help prevent osteoporosis