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Cell Signaling
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General Principles of Cell Signaling
signaling cell => signaling molecule binds to receptor molecule on target cell
Signaling Distances: => Four Types of Signaling
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Endocrine
Paracrine
Neuronal
Contact Dependent
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T16-1
testosterone,
TGF-b, acetylcholine,
Delta
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F.16-3
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
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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
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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
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Based on Ability to Cross Plasma Membrane
F.16-9
• Cross Plasma Membrane (hydrophobic)
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– 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
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F16-11 & 12
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16_10_Nitric_oxide.jpg
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16_11_phobic_hormone.jpg
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16_12_cortisol.jpg
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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
– Enzyme-Linked Receptors
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F16-16
F16-14C
16_14_3_basic_classes.jpg
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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:
– GDP bound = inactive,
– GTP bound = active
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F16-15B
Cell Signaling
G-Protein Linked Receptors
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•
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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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16_18_Gprot_subunit.jpg
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Cell Signaling
G-Protein Linked Receptors
• Action mechanisms
– Some regulate ion channels
F16-19
– 2nd messenger = cAMP
F16-24
• Some activate membrane-bound enzymes => increase “2nd
messengers”
F16-20
•
adenyl cyclase => ATP to cAMP
cAMP phosphodiesterase => cAMP to ATP
cAMP dependent protein kinase activation by Camp
cAMP => both rapid and slow responses
– 2nd messengers = IP3 & DAG
phospholipase c => IP3 & DAG
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 membrane
activated PKC => many effects
– 2nd messenger = Ca+2
free Ca+2 => many effect via Ca+2 binding proteins
e.g. calmodulin & calmodulin dependent protein kinases
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F16-23
F16-25
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
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•
•
Transmembrane proteins
cytoplasmic domain is enzyme or interacts w enzyme
When ligand is soluble signaling protein, action usually
gene regulation – slow
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Receptor Tyrosine Kinases (= RTK)
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Ligand binding =>
dimerization of RTK subunits =>
activate kinase activity =>
binding of intracellular signaling proteins
protein phosphatases remove P from RTK
Intracellular signaling proteins include
F16-30
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
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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 Pathway
• RTKs of the TGF-b superfamily
F16-37
– 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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•
SIGNALING
PATHWAYS CAN BE
HIGHLY
INTERCONNECTED
Cell Signaling
F16-38
•
(like nerve networks in brain or
microprocessors in a computer)
•
“... a major challenge
to figure out how
cell communication
pieces fit together
to allow cells to
integrate
environmental
signals and to
respond
appropriately”
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