cell signalling

• Cell signalling

  Signals originating outside of cells can be perceived and transduced to cause changes in cellular behaviour
• Types of cell signalling


  • Endocrine - long distance signalling via the bloodstream
  • Paracrine - local signalling over a short distance
  • Neuronal - targeted signalling over a very short distance
  • Contact-dependent - signal and receptors remain in cell membranes
• Receptors


  Can be at the cell surface or within the cell depending on signal molecule properties
• A limited set of extracellular signals can produce a huge variety of cell behaviors
• An animal cell has a multitude of different cell surface receptors and depends on a huge array of signalling molecules
• Loss of ability to respond to signals or loss of survival signals themselves

  Stimulates apoptosis
• Cell response to a signal

  Can be fast (change in target protein conformation) or slow (initiation of target gene transcription)
• Cell-surface receptors relay extracellular signals via intracellular signalling pathways

  1. Intracellular signalling molecules are activated in turn in a 'signal cascade' and they stimulate effector proteins which carry out a variety of cellular responses

  2. Second messenger molecules are involved
• In positive feedback

  Protein T stimulates production of protein Y which, in turn, stimulates further production of T. This leads to a very large response to a signal.
• In negative feedback


  Y inhibits further production of T. This leads to a short response.
• Intracellular signalling proteins


  Act as molecular switches via phosphorylation or GTP-binding
• We have looked at the activity of guanine nucleiotide exchange factors (GEFs) and GTPase activating proteins (GAPs) in previous lectures
• Cell-surface receptors fall into three main classes: Ion channel-coupled, G-proteins, and Enzyme-coupled
• G proteins


  Active when bound to GTP, inactive when bound to GDP
• G proteins


  • Some directly regulate ion channels
  • Many activate membrane-bound enzymes that produce small messenger molecules
  • The cyclic AMP signalling pathway can activate enzymes and turn on genes
  • The inositol phospholipid pathway triggers a rise in intracellular Ca2+
• GPCR-triggered intracellular signalling cascades


  • Can achieve astonishing speed, sensitivity, and adaptability
• GPCR


  • Cytoplasmic portion binds a G protein inside the cell
  • Have 7 membrane-spanning α-helicies
  • Stimulation activates G protein subunits
• All eukaryotic cells have the same basic set of membrane-enclosed organelles
• G protein action in the cell


  1. Some directly regulate ion channels

  2. Many activate membrane-bound enzymes that produce small messenger molecules (second messengers)

  3. Cyclic AMP (cAMP) signalling pathway can activate enzymes and turn on genes

  4. Epinephrine signals glycogen breakdown via a complex cascade
• The plasma membrane encloses the cytosol
• Evolution of membrane-enclosed organelles


  1. Invagination of the plasma membrane (nuclear membrane and ER)

  2. Endosymbiosis (mitochondria and plastids)
• Signal amplification in the epinephrine signalling cascade - 1 molecule of adrenaline = 10,000 molecules of glucose
• Inositol phospholipid pathway


  1. G protein activates phospholipase C

  2. 1,4,5 IP3 is released and activates a Ca2+ channel in the ER

  3. Ca2+ and diacylglycerol activate protein kinase C
• Topologically equivalent spaces


  Cellular compartments between which molecules can traverse without having to cross membranes
• Signal sequences


  Direct proteins to the correct cellular address
• Single-pass transmembrane protein


  A protein with a cleaved ER signal sequence and a single internal hydrophobic domain that remains in the lipid bilayer
• Ca2+ signalling


  • A Ca2+ signal triggers many biological processes
  • A Ca2+ wave is triggered by sperm entry into an egg cell and propagates quickly throughout the cell
• Sorting receptors


  Direct proteins to the correct cellular address
• Stop transfer signal


  The orange transmembrane domain that remains anchored within the ER membrane
• Nitric oxide (NO) signalling

  A GPCR signalling pathway generates a dissolved gas that carries a signal to adjacent cells
• Ways proteins can move between compartments

  • Gated transport
  • Transmembrane transport
  • Vesicular transport
• Internal ER signal sequence


  Can act as a start transfer sequence
• GPRC-triggered intracellular signalling cascades can achieve astonishing speed, sensitivity, and adaptability
• Transport from the ER through the Golgi apparatus

  1. Proteins leave the ER in COPII-coated transport vesicles

  2. Proteins are further modified and sorted in the Golgi apparatus

  3. ER membrane proteins destined for export to the Golgi interact with adaptor proteins of the inner COPII coat

  4. Some soluble proteins in the ER lumen interact with membrane-bound receptors to enter the budding vesicle

  5. Other soluble proteins enter the vesicle by bulk flow
• Single-pass transmembrane proteins


  • Can result when the protein has a single internal ER signal sequence which remains in the lipid bilayer
  • The protein's N-terminus can project into the cytosol (A) or into the ER lumen (B)
• Gated transport - Transport of molecules between cytosol and nucleus

  1. Nuclear pores are gated

  2. Large molecules need to be chaperoned to transit between nucleoplasm and cytoplasm

  3. Nuclear transport receptors (importins and exportins) bind to cargo and mediate translocation across NPC
• Enzyme-coupled receptors


  • Activated receptor tyrosine kinases (RTKs) recruit a complex of intracellular signalling proteins
  • Most RTKs activate the monomeric GTPase Ras
  • RTKs activate PI 3-kinase to produce lipid docking sites in the plasma membrane
  • Some extracellular signal molecules cross the plasma membrane and bind to intracellular receptors
  • Plants make use of receptors and signalling strategies that differ from those used by animals
  • Protein kinase networks integrate information to control complex cell behaviors
• Multipass transmembrane proteins

  Proteins that span the ER membrane multiple times
• Enzyme-coupled receptors - Receptor tyrosine kinases (RTKs)


  Activated RTKs recruit a complex of intracellular signalling proteins
• Transport from the ER through the Golgi apparatus

  1. Vesicular tubular clusters mediate transport from the ER to the Golgi apparatus

  2. Small vesicles can fuse into larger compartments as long as they have matching SNARE protein pairs

  3. This is called homotypic membrane fusion and leads to formation of larger secretory compartments called vesicular tubular clusters

  4. Vesicular tubular clusters move via interaction with microtubules to mediate transport between ER and Golgi

  5. COPI-coated vesicles bud from these clusters to transport cargo in the retrograde direction back to the ER