Chapter 15: Cell Signaling 

Principles of cell signaling

  • Extracellular signals can act over short or long distance
    • contact-dependent
    • have to shake each other’s hands
    • paracrine
    • signal neighbor that is a different cell type
    • within the same tissue
    • autocrine
    • signaling same cell type
    • synaptic
    • endocrine
    • involves bloodstream
  • Extracellular signal molecules bind to specific receptors
    • cell-surface receptors
    • hydrophilic signal molecule
    • intracellular receptors
    • small hydrophobic signal molecule
    • hormones
  • each cell is programmed to respond to specific combinations of extracellular signals and make decisions accordingly
    • survival signals necessary to avoid apoptotic
  • signals are pleiotropic
  • pleiotropic: many different results
    • Ex. Acetylcholine
    • depending on cell type, can lead to decreased rate of firing, secretion, contraction, and more
    • Ex. vitamin D
    • calcium regulation, transcription, and more (unknown)
  • 3 major classes of cell-surface receptor proteins
    • ion-channel-coupled receptors
    • Ligan-gated channel
    • fast
    • G-protein-coupled receptors
    • senses (taste, smell, etc.)
    • some neurotransmitters
    • Enzyme-coupled receptors
    • linked to cancer
    • either signals that are enzymes or have a friend that is an enzyme that it talks to
  • A sequence of 2 inhibitory signals produces a positive signal
  • intracellular signaling complexes form at activated cell-surface receptors
  • molecular interaction domains mediate interactions between intracellular signaling proteins
    • PH: pleckstrin homology
    • loves lipids
    • PTB: Phosphotyrosine bonding
    • SH2: sark homology 2
    • bind to phosphotyrosine
  • speed of a response depends on turnover of signaling molecules
  • positive and negative feedback
    • positive harder to regulate
    • we see a lot of negative

Signaling through G-protein-coupled receptors

  • heterotrimeric G proteins relay signals from GPCRs
    • ligan binds and changes shape
    • bumps into G protein
    • 3 different subunits
  • some G proteins regulate the production of cyclic AMP (cAMP)
    • activates other things
  • cAMP dependent protein kinase (PKA) mediates most of effects of cAMP
    • cAMP Response Element Binding (CREB)
    • PKA phosphorylates other things (metabolism), glycogen break down to glucose
    • caffeine blocks cAMP phosphodiesterase, body adapts by making less
  • agonist: stimulates receptor
  • antagonist: blocks receptor
  • some G proteins signal via phospholipids
  • phospholipase C
    • substrate PI (4,5) P2
    • cleaves to create 2 second messengers
    • 1 with 2 long lipid tails (diacylglycerol)
      • activates protein kinase C
    • 1 goes all around cytoplasm (IP3)
      • releases Ca2+ from the ER
  • calmodulin
    • activated when there is cytoplasmic calcium
  • Ca2+/calmodulin-dependent protein kinases mediate many responses to Ca2+ signals
  • smell and vision depend on GPCRs that regulate ion channels
  • visual transduction
    • 1 photon → 1 mV change in membrane potential
  • nitric oxide
  • GPCR desensitization depends on receptor phosphorylation

Enzyme linked receptors

  • RTK’s
    • Receptor Tyrosine Kinases
    • phosphorylate each other
    • work in pairs
    • serve as “docking stations” for signaling proteins
  • Monomeric GTPase Ras mediates signaling by most RTKs
    • mess up → cancer
    • up to 60% of cancers have messed up Ras
  • Bad: pro apoptosis; regularity subunit of Bcl-2
  • Bcl2: anti apoptosis; keeps mt from leaving
  • mTORC
  • RTK and GPCR overlap
  • JAK-STAT signaling
    • cytokine
    • signaling molecule
    • immunologically related
    • either makes more of itself or sends cytokine out
  • hedgehog proteins

Alternative signaling routes in gene regulation

  • NFkB
  • \