topic 14-11 14 cell signaling. topic 14-12 focus on higher order vertebrates multiple levels of cell...
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14 Cell Signaling
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Focus on higher order vertebratesMultiple levels of cell signaling
EndocrineCells producing signaling factors are physically separatedMessenger molecules are secretedCarried in blood or extra-cellular fluidTarget Cells
Membrane receptorsIntracellular actions via signal cascade
Cytoplasmic receptorsUsually a specific transport system to move signal molecule-receptor complex to nucleus – response element
Cell Signaling
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Multiple levels of cell signalingParacrine
Features most similar to endocrine signaling
Major differenceTarget 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
AutocrineCellular self-signaling
Cell Signaling
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Multiple levels of cell signalingCell Signaling
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Multiple levels of cell signalingAdhesion
Cell to cell interactionCells identify cell-types nearby
Cell to extra-cellular matrix interactionCells identify their physical environment
Cell Signaling
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Forms of signaling molecules
GassesNO
CO
Steroid HormonesTestosterone
Estradiol
Progesterone
GlucocorticoidsCortisol
MineralocorticoidsAldosterone
Cell Signaling
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Forms of signaling moleculesNeurotransmitters
Cell Signaling
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Forms of signaling molecules
Peptide Hormones and Growth Factors
Cell Signaling
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Forms of receptorsSteroid receptors
Present in the cytoplasm or localized in the nucleusRecall Glucocorticoid receptor – interaction with the GRE
Cell Signaling
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Forms of receptorG protein-coupled receptors
Seven transmembrane helix familyProgesterone R
-adrenoceptors
Cell Signaling
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Cell Signaling
The 2 adrenoceptor
- S- S-
Extracellular
domain
Intracellulardomain
Transmembrane domain
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Forms of receptorsTyrosine Kinase Receptors
Not only a receptorAlso an enzyme
Tyrosine kinase
ExamplesInsulin RIGF Type 1 REGF
Cell Signaling
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Forms of receptorsCytokine superfamily receptors
No catalytic domain
Interact with nonreceptor protein-tyrosine kinases
Src family
JAK family
Cell Signaling
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The Insulin Receptor Cascades
IR is a receptor tyrosine kinase
A family of receptors involved in cell growth and differentiation
TetramerTwo and two subunits
Cell Signaling
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The Insulin Receptor CascadesAbsence of insulin – tyrosine kinanse is inactiveBinding causes a conformational changeActivated tyrosine kinase transfers phosphate groups to:
Specific tyrosines of alternate subunit autophosphorylationA soluble protein substrate (family) – insulin receptor substrates (IRSs)
Cell Signaling
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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
Cell Signaling
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The Insulin Receptor Cascades Insulin receptor substrates (IRSs)
Insulin may signal along several independent pathways
One of these is phosphatidylinositol-3-hydroxy kinase (PI3K)
Cell Signaling
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Cell SignalingThe Insulin Receptor Cascades
Phosphatidylinositol-3-hydroxy kinase (PI3K)
Catalyses phosphate addition to the 3’ position on the sugar ring of phosphatidyl inositolProducts:
PI 3,4-biphosphate (PIP2)PI 3,4,5-triphosphate (PIP3)Remain in the cytosolic leaflet of lipid bilayerMembrane-bound lipid messengers
Diverse functions in many cell types
Activation of protein kinase B via its PH domain
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Cell SignalingThe Insulin Receptor Cascades
Phosphatidylinositol-3-hydroxy kinase (PI3K)
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Cell SignalingThe Insulin Receptor Cascades
Protein kinase BPIP2 recruits PKB to plasma membrane
Binding – conformational changeTransfer of glucose transporters to the plasma membrane
Increased protein synthesis
Glycogen synthase
Glucose to glycogen
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The Insulin Receptor Cascades Insulin receptor substrates (IRSs)
Insulin may signal along several independent pathways
Another IRS pathway: Ras – cell growth and proliferation
Cell Signaling
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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 RasSmall G-protein
At inner surface of plasma membrane
Lipid group embedded in inner leaflet
Cell Signaling