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Copyright © 2005 Pearson Prentice Hall, Inc.
•http://aimediaserver.com/studiodaily/videoplayer/?src=harvard/harvard.swf&width=640&height=520
Copyright © 2005 Pearson Prentice Hall, Inc.
Cell Signaling• General Principles of Cell Signaling
– signaling cell => signaling molecule binds to receptor molecule on target cell
Signaling Distances: => Four Types of Signaling F.16-3
• Endocrine• Paracrine• Neuronal• Contact Dependent
• T16-1 • testosterone, • TGF-b, acetylcholine, • Delta
Copyright © 2005 Pearson Prentice Hall, Inc.
Cell Signaling• Receptor:
– Each Target Cell Responds to Limited Set of Signals
(origin of complexity)
– Must have receptor molecule for the signaling molecule
(thousands of receptors)
– Different receptors for same signal on different cells
F16-5 A & C or F16-5 B & C
•
Copyright © 2005 Pearson Prentice Hall, Inc.
Cell Signaling• Intracellular
Signaling Pathways: – Same receptor
molecule can interact w/many intracellular relay systems so same signal & same receptor => different effects in different cells
F16-5A & B
– Same relay system many act on many different intracellular targets
F16-7
Copyright © 2005 Pearson Prentice Hall, Inc.
Cell Signaling
• Target Cell Action:Depends upon ---- F16-6
– Signals That are Present– Receptors That Target Cell Synthesizes– Intracellular Relay Systems = Signaling Cascades
That Target Cell Synthesizes– Intracellular Targets That Target Cell Synthesizes
F16-8
• Any target cell type at any one time has only a subset of all possible – Receptors, – Intracellular Relay Systems, – Intracellular Targets
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Cell Signaling
• Signaling Cascades: Critical Functions
• pp. 539 & 540
• (be able to apply each function to components of the signaling cascades we study)
• Transduce Signal• Relay signal from point of reception to
point of response production• Amplify F16-29
• Distribute signal to >1 process simultaneously
• Modulate signal to fit other internal & external conditions
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Cell Signaling
• Extracellular Signaling Molecules: • Two Types of Extracellular Signaling Molecules• Based on Ability to Cross Plasma Membrane
F.16-9
• Cross Plasma Membrane (hydrophobic)– NO directly activate intracellular enzymes
F16-10
• vascular endothelial cells release NO• activates guanyl cyclase in smooth muscle
=> relaxation => vasodilation• guanyl cyclase: GTP = cGMP• nitroglycerine, erection, Viagra (blocks cGMP
reakdown)– Steroid Hormones F16-11 & 12
•
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Cell Signaling
• Ligand for Cell Surface Receptor • (hydrophilic: don’t cross plasma membrane)
F16-1
– Ion-Channel-Linked Receptors F16-14A
• convert chemical to electrical signals
– G-protein-linked Receptors F16-14B, & F16-17
• ligand binding => G-Protein activation by exchange bound GDP for GTP
• Common structure = 7-pass membrane protein F16-16
– Enzyme-Linked ReceptorsF16-14C
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Cell Signaling
• Intracellular Signaling Molecules – Many are Molecular Switches– switched on by signaling molecule, must also be turned
off
• Most common switching mechanisms T16-2 nicotine, morphine & heroin
– phosphorylation F16-15A
– signal activated kinase; – dephosphorylation – phosphatase
– GTP binding proteins: F16-15B
– GDP bound = inactive, – GTP bound = active
Copyright © 2005 Pearson Prentice Hall, Inc.
Cell SignalingG-Protein Linked Receptors
• Largest family of cell-surface receptors – 100s of members
• 7-pass Transmembrane Proteins F16-16
• Ligand binding Activates G-Protein subunits
F16-17
Inactivated by hydrolysis of its own bound GTP F16-18 cholera toxin prevents this; G protein stays on => water & ion loss
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Cell SignalingG-Protein Linked Receptors
• Action mechanisms– Some regulate ion channels F16-19
• Some activate membrane-bound enzymes => increase “2nd messengers” F16-20
– 2nd messenger = cAMP F16-24• adenyl cyclase => ATP to cAMP
cAMP phosphodiesterase => cAMP to ATPcAMP dependent protein kinase activation by CampcAMP => both rapid and slow responses F16-23
– 2nd messengers = IP3 & DAGphospholipase c => IP3 & DAG F16-25
IP3 => opens ER Ca+2 channels . >>>> cytoplasmic Ca+2.> free Ca+2 => many effects
DAG (w free Ca+2) => activated PKC to inner face of membraneactivated PKC => many effects
– 2nd messenger = Ca+2free Ca+2 => many effect via Ca+2 binding proteins
e.g. calmodulin & calmodulin dependent protein kinases
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Some regulate ion channels
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Some activate membrane-bound enzymes => increase “2nd
messengers”
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2nd messenger =
cAMP
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2nd messenger =
cAMP
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2nd messengers =
IP3 & DAG
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Cell Signaling Enzyme Linked Receptors
• Transmembrane proteins• cytoplasmic domain is enzyme or interacts w
enzyme• When ligand is soluble signaling protein, action
usually gene regulation – slow
• Receptor Tyrosine Kinases (= RTK)– Ligand binding => – dimerization of RTK subunits => – activate kinase activity => – binding of intracellular signaling proteins F16-30
– protein phosphatases remove P from RTK
• Intracellular signaling proteins include– a phospholipase that, like PLC, activates IP3 pathway– a PI 3-kinase that PO4s membrane IPLs, then bind other
signaling proteins– Ras: important in loss of control of cell division, & thus in
cancer
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Cell Signaling Enzyme Linked Receptors
• All RTKs Activate Ras – Ras = One of lg family of monomeric GTP Binding Proteins
F16-31
• NOT trimeric like G protein• resembles a subunit of trimeric G proteins• Activated by binding GTP• Inactivated by hydrolysis of its own bound GTP
• Activated Ras activates MAP kinase phosphorylation cascade F16-32
• Effect of inactivating Ras => cell ignores signals to divide• Effects of permanent activation of Ras => cell acts as if
constantly receiving mitogens• Mutant Ras in cancer cells (~30% of all human cancers have
mutant) => constantly “on”
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Cell Signaling Enzyme Linked Receptors
• Some activate fast track to the nucleus– Cytokines & a few hormones – JAK-STAT Pathway
• Receptor kinase activation => activation & translocation to nucleus of latent gene regulatory proteins held at plasma membrane F16-36
– SMAD PathwayF16-37
• RTKs of the TGF-b superfamily– important in animal development– Auto phosphorylation => recruits & activates a SMAD,
which releases, binds a different SMAD, move to nucleus & takes part in regulating gene activity
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Cell Signaling• SIGNALING PATHWAYS CAN BE HIGHLY INTERCONNECTED
F16-38
• (like nerve networks in brain or microprocessors in a computer)
• “... a major challenge to figure out how cell communication pieces fit togetherto allow cells to integrate environmental signals and to respond appropriately”
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