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Cell signalling


									Cell signalling

 26 March 2007
• No cell lives in isolation

• In all multicellular organisms, survival depends on an
  elaborate intercellular communication network that
  coordinates the growth, differentiation, and metabolism
  of the multitude of cells in diverse tissues and organs.

• Errors in cellular information processing are responsible
  for diseases such as cancer, autoimmunity, and diabetes.
  By understanding cell signaling, diseases can be treated
  effectively and, theoretically, artificial tissues could be
• Cells within small groups often communicate by direct
  cell-cell contact. Specialized junctions in the plasma
  membranes of adjacent cells permit them to exchange
  small molecules and to coordinate metabolic responses;
  other junctions between adjacent cells determine the
  shape and rigidity of many tissues.
• In addition, the establishment of specific cell-cell
  interactions between different types of cells is a
  necessary step in the development of many tissues. In
  some cases a particular protein on one cell binds to a
  receptor protein on the surface of an adjacent target
  cell, triggering its differentiation.
• Eukaryotic microorganisms
  – Pheromones coordinate
     • Sexual mating
     • Differentiation
• Plants, animals
  – Extracellular signaling controls
     • Metabolic processes
     • Growth and differentiation
     • Protein synthesis
• Signal molecules produce responses in
  target cells that have receptors.
• In multicellular organisms
  –   Chemicals
  –   Small molecules (aa., lipid derivatives)
  –   Peptides
  –   proteins
• Some diffuse and bind to intracellular
  – Steroids, retinoids, thyroxine
Cell signaling pathways
         Signal transduction

– Overall processes converting a signal into
  cellular responses
                 Cell Signaling

• Steps involved are:
  –   Synthesis
  –   Release from signaling cells
  –   Transport to target cells
  –   Binding to receptor and activation
  –   Signal transduction by activated receptor
  –   Specific changes
  –   Removal of signal (termination)
• Receptor activation
  – Secreted or membrane bound molecules
     • Hormones, growth factors, neurotransmitters,
  – Changes in the concentration of metabolites
     • Oxygen or nutrients
  – Physical stimuli
     • Light, touch, heat
  Three types of signaling in
– Endocrine
   • hormones
– Paracrine
   • Neurotransmitters
   • Growth factors
– Autocrine
   • Growth factors
     (cultured cells, tumor
      Ligand binding and effector specificity

• Each receptor binds only a single ligand
  or a group of closely related molecules.
  However, many signaling molecules bind
  to multiple types of receptors

• Acetylcholine binds to different receptors
  on muscle cells (contraction), heart
  muscle cells (inhibition of contraction)
  and pancreas acinar cells (exocytosis of
  secretory granules), respectively
• Different receptors of the same class that
  bind different ligands generate the same
  cellular response
• In liver, ACTH, epinephrine and glucagon
  bind to different GPCRs; but all three
  activate the same signaling pathway
     Intracellular signal transduction

• Many receptors transmit signals via
  second messengers
• They rapidly alter the activity of enzymes
  or non-enzymatic proteins
  – Ca2+ triggers contraction in muscle cells
  – Exocytosis of secretory vesicles in endocrine
  – cAMP generates different metabolic changes
    in different type of cells
            Regulation of signaling

• External signal decreases
  – Degradation of second mesenger
• Desensitization to prolonged signaling
  – Receptor endocytosis
• Modulation of receptor activity
  – Phosphorylation
  – Binding to other proteins
  Hormones Can Be Classified Based on
  Their Solubility and Receptor Location
• Most hormones fall into three broad
• (1) small lipophilic molecules that diffuse
  across the plasma membrane and interact
  with intracellular receptors;
• (2) hydrophilic or (3) lipophilic molecules
  that bind to cell-surface receptors.
• Recently, nitric oxide, a gas, has been
  shown to be a key regulator controlling
  many cellular responses
     Classification of receptors
• Intracellular receptors (for lipid soluble
     • function in the nucleus as transcription factors to
       alter the rate of transcription of particular genes.
• Plasma membrane receptors (for lipid
  insoluble messengers)
     • Receptors function as ion channels
     • receptors function as enzymes or are closely
       associated with cytoplasmic enzymes
     • receptors that activate G proteins which in turn act
       upon effector proteins, either ion channels or
       enzymes, in the plasma membrane.
   Hormones bind to intracellular
receptors and to cell-surface receptors
Nitric oxide
       Intracellular Receptors
• Extracellular signal molecules are small,
  lipid-soluble hormones such as steroid
  hormones, retinoids, thyroid hormones,
  Vitamin D. (Made from cholesterol)
• These hormones diffuse through plasma and
  nuclear membranes and interact directly
  with the transcription factors they control.
Sequence similarities and three functional regions

– N-terminal region of variable length (100-500 aa); in some
  receptors portions of this region act as activation domain
– At the center, DNA binding domain, made of a repeat of C4-zinc
  finger motif
– Near the C-terminal end, an hormone binding domain, which may
  act as an activation or repression domain.
The intracellular receptor superfamily.
  Nuclear receptor response elements
• Some characteristic sites of DNA are called
  response elements and can bind several nuclear
• These repeat regions are arranged either as an
  invert repeat, or direct repeat.
  – Inverted repeat: glucocorticoid response element;
    estrogen response element
     • Repeats are separated by any three bases, implicating
       symmetrical binding of the receptor homodimer to DNA
• Receptors for vitaminD, retinoic acid and
  thyroid hormone bind to direct repeats as
• Second component of the heterdimer is
  RXR monomer (i.e, RXR-RAR; RXR-
• The specifity of the binding is determined
  by the spacing between repeats.
 Regulation of transcription activity

• Regulatory mechanisms differ for hetero-
  dimeric and homodimeric receptors
• Heterodimeric receptors are exclusively
  nuclear; without ligand, they repress
  transcription by binding to their cognate
  sites in DNA
  – They do so by histone deacetylation
• Homodimeric receptors are cytoplasmic in the
  absence of ligands.
• Hormone binding leads to nuclear translocation
  of receptors
• Absence of hormone causes the aggregation of
  receptor as a complex with inhibitor proteins,
  such as Hsp90
Early primary response (A) and delayed secondary response (B) that
result from the activation of an intracellular receptor protein.

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