Cell signalling

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Cell signalling

• 26 March 2007

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Overview

• 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
  built.

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• 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.

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• Eukaryotic microorganisms
• Pheromones coordinate
• Sexual mating
• Differentiation
• Plants, animals
• Extracellular signaling controls
• Metabolic processes
• Growth and differentiation
• Protein synthesis

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• 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 receptors
• Steroids, retinoids, thyroxine

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Cell signaling pathways
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Signal transduction

• Overall processes converting a signal into
  cellular responses

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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)

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• Receptor activation
• Secreted or membrane bound molecules
• Hormones, growth factors, neurotransmitters,
  pheromones
• Changes in the concentration of metabolites
• Oxygen or nutrients
• Physical stimuli
• Light, touch, heat

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Three types of signaling in animals

• Endocrine
• hormones
• Paracrine
• Neurotransmitters
• Growth factors
• Autocrine
• Growth factors (cultured cells, tumor cells)

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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

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• 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 (cAMP)

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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
  cells
• cAMP generates different metabolic changes in
  different type of cells

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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

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Receptors
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Hormones Can Be Classified Based on Their
Solubility and Receptor Location

• Most hormones fall into three broad categories
• (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

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Classification of receptors

• Intracellular receptors (for lipid soluble
  messengers)
• 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.

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Hormones bind to intracellular receptors and to
cell-surface receptors
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Nitric oxide
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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.

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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.

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The intracellular receptor superfamily.
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Nuclear receptor response elements

• Some characteristic sites of DNA are called
  response elements and can bind several nuclear
  receptors.
• 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

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• Receptors for vitaminD, retinoic acid and thyroid
  hormone bind to direct repeats as heterodimers,
• Second component of the heterdimer is RXR monomer
  (i.e, RXR-RAR RXR-VDR)
• The specifity of the binding is determined by the
  spacing between repeats.

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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

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• 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

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Early primary response (A) and delayed secondary
response (B) that result from the activation of
an intracellular receptor protein.