14 Cell Signaling

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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 molecule-receptor 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
b
The
adrenoceptor
2
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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 protein-tyrosine
  kinases
• Src family
• JAK family

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Cell Signaling

• The Insulin Receptor Cascades
• IR is a receptor tyrosine kinase
• A family of receptors involved in cell growth and
  differentiation
• Tetramer
• Two a and two b subunits

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Cell Signaling

• The Insulin Receptor Cascades
• Absence of insulin tyrosine 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) 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 (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
• Activation of protein kinase B via its PH domain

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Cell Signaling

• The Insulin Receptor Cascades
• Phosphatidylinositol-3-hydroxy 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