14 Cell Signaling
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Cell Signaling
Focus on higher order vertebrates
Multiple levels of cell signaling
Endocrine
Cells producing signaling factors are physically separated
Messenger molecules are secreted
Carried in blood or extra-cellular fluid
Target Cells
Membrane receptors
Intracellular actions via signal cascade
Cytoplasmic receptors
Usually a specific transport system to move signal moleculereceptor complex to nucleus – response element
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Cell Signaling
Multiple levels of cell signaling
Paracrine
Features most similar to endocrine signaling
Major difference
Target cell found in the same tissue
Messenger molecules carried across extra-cellular matrix or
through extra-cellular fluid
Many growth factors are associated with the matrix
Autocrine
Cellular self-signaling
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Cell Signaling
Multiple levels of cell signaling
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Cell Signaling
Multiple levels of cell signaling
Adhesion
Cell to cell interaction
Cells identify cell-types nearby
Cell to extra-cellular matrix interaction
Cells identify their physical environment
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Cell Signaling
Forms of signaling
molecules
Gasses
NO
CO
Steroid Hormones
Testosterone
Estradiol
Progesterone
Glucocorticoids
Cortisol
Mineralocorticoids
Aldosterone
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Cell Signaling
Forms of signaling molecules
Neurotransmitters
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Cell Signaling
Forms of
signaling
molecules
Peptide
Hormones and
Growth Factors
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Cell Signaling
Forms of receptors
Steroid receptors
Present in the
cytoplasm or localized
in the nucleus
Recall Glucocorticoid
receptor – interaction
with the GRE
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Cell Signaling
Forms of receptor
G protein-coupled receptors
Seven transmembrane helix family
Progesterone R
b-adrenoceptors
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Cell Signaling
Extracellular
domain
- S- S-
Transmembrane
domain
Intracellular
domain
The b2 adrenoceptor
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Cell Signaling
Forms of receptors
Tyrosine Kinase
Receptors
Not only a receptor
Also an enzyme
Tyrosine kinase
Examples
Insulin R
IGF Type 1 R
EGF
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Cell Signaling
Forms of receptors
Cytokine superfamily
receptors
No catalytic domain
Interact with
nonreceptor proteintyrosine kinases
Src family
JAK family
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Cell Signaling
The Insulin Receptor
Cascades
IR is a receptor tyrosine
kinase
Bla
A family of receptors
involved in cell growth and
differentiation
Tetramer
Two a and two b subunits
nk
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Cell Signaling
The Insulin Receptor Cascades
Absence of insulin – tyrosine Bla
kinanse is inactive
Binding causes a conformational
change
Activated tyrosine kinase transfers
phosphate groups to:
Specific tyrosines of alternate subunit
autophosphorylation
A soluble protein substrate (family)
–
nk
insulin receptor substrates (IRSs)
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Cell Signaling
The Insulin Receptor Cascades
Insulin receptor substrates (IRSs)
Phosphorylated IRS – a single function – to activate
downstream messengers
Like several other signaling proteins contains an SH2 domain
SH2 domains have high affinity for phosphorylated tyrosines
Possession of these SH2 modules allows proteins in a signal
cascade to be strung together
Different cells contain different protein messengers with SH2
domains
Insulin signaling varies in effect depending on cell type
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Cell Signaling
The Insulin Receptor Cascades
Insulin receptor substrates (IRSs)
Insulin may signal along several independent
pathways
One of these is phosphatidylinositol-3-hydroxy
kinase (PI3K)
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Cell Signaling
The Insulin Receptor Cascades
Phosphatidylinositol-3-hydroxy kinase
Blan
(PI3K)
Catalyses phosphate addition to the 3’ position
on the sugar ring of phosphatidyl inositol
Products:
PI 3,4-biphosphate (PIP2)
PI 3,4,5-triphosphate (PIP3)
Remain in the cytosolic leaflet of lipid bilayer
Membrane-bound lipid messengers
Diverse functions in many cell types
k
Activation of protein kinase B via its PH
domain
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Cell Signaling
The Insulin Receptor
Cascades
Phosphatidylinositol-3hydroxy kinase (PI3K)
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Cell Signaling
The Insulin Receptor Cascades
Protein kinase B
PIP2 recruits PKB to plasma membrane
Binding – conformational change
Transfer of glucose transporters to the plasma
membrane
Increased protein synthesis
Glycogen synthase
Glucose to glycogen
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Cell Signaling
The Insulin Receptor Cascades
Insulin receptor substrates (IRSs)
Insulin may signal along several independent
pathways
Another IRS pathway: Ras – cell growth and
proliferation
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Cell Signaling
The Insulin Receptor Cascades
Ras
ras gene - originally discovered as a viral
oncogene
Also part of the normal genome
Many tumor cells contain a mutant ras
Protein product Ras
Small G-protein
At inner surface of plasma membrane
Lipid group embedded in inner leaflet
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