Ch26 Cell Signalling

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Ch26 Cell Signalling

• Yuki Juan
• NTU
• May 19, 2003

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Outline

• Introduction
• What are the singalling molecules
• Intracellular receptor-mediated responses
• Membrane receptor-mediated singalling systems
• Tyrosine kinase-associated receptors
• The G-protein-coupled receptors
• Singal transduction pathway using cGMP as second
  messenger

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Outline

• Introduction
• What are the singalling molecules
• Intracellular receptor-mediated responses
• Membrane receptor-mediated singalling systems
• Tyrosine kinase-associated receptors
• The G-protein-coupled receptors
• Singal transduction pathway using cGMP as second
  messenger

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Term Definition

• Second messengers
• A small intracellular regulatory molecules which
  causes cell responses.
• E. g. Cyclic AMP

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Outline of Receptor-mediated Signalling
receptor
Target cell
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Cellular Responses to Singals
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Outline

• Introduction
• What are the singalling molecules
• Intracellular receptor-mediated responses
• Membrane receptor-mediated singalling systems
• Tyrosine kinase-associated receptors
• The G-protein-coupled receptors
• Singal transduction pathway using cGMP as second
  messenger

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What Are The Singalling Molecules

• Neurotransmitters
• Endocrine Howmones (Table 26.1)
• The classical singalling molecules
• Growth factors and cytokines
• Regarded as singals
• Which may induce cell growth and division or
  inhibit it
• May affect differentiation
• Instruct the cell to undergo apoptosis
• Vitamins A and D derivatives
• Retinoic acid (Vit A) singalling molecule in
  embryonic development and normal cell growth
• Vitamin D3 control of genes involved in calcium
  absorption from the intestine

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How Hormone Binding To Surface Receptor
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Growth Factors and Cytokines

• Most cytokines/growth factors are paracrine, some
  are autocrine
• The first known growth factor was
  platelet-derived growth factor (PDGF)
• PDGF stimulates cell division and repair
• Epidermal growth factor (EGF)
• stimulates the growth of Skin cells
• Colony stimulating factors (CSFs)
• Stimulate the growth of colonies of white cells
  on the culture plates.

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Autocrine Singals and Paracrine Signals

• Autocrine signals affect the cell producing them.
• Paracrine singals diffuse only a short distance
  to affect nearby cells

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Outline

• Introduction
• What are the singalling molecules
• Intracellular receptor-mediated responses
• Membrane receptor-mediated singalling systems
• Tyrosine kinase-associated receptors
• The G-protein-coupled receptors
• Singal transduction pathway using cGMP as second
  messenger

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The Structures of the Lipid-soluble signalling
Molecules

• They can combine with their specific receptors
  which exist inside the cell rather than in the
  membrane

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Gene Activation by Steroid Hormones

• The glucocorticoid receptor one of a superfamily
  of steroid/thyroxine receptors
• Binding to DNA sites by zinc fingers

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Outline

• Introduction
• What are the singalling molecules
• Intracellular receptor-mediated responses
• Membrane receptor-mediated singalling systems
• Tyrosine kinase-associated receptors
• The G-protein-coupled receptors
• Singal transduction pathway using cGMP as second
  messenger

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Central Principle of Control by Many
Extracellular Signals

• Key processes in cell signalling are protein
  phosphorylation by protein kinases and reversal
  by protein phosphatases

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Tyrosine Phosphorylation by Tyrosine Kinase
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Tyrosine Kinase Type of Receptors and The Other
Type of Signalling
Adaptor molecules
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Outline

• Introduction
• What are the singalling molecules
• Intracellular receptor-mediated responses
• Membrane receptor-mediated singalling systems
• Tyrosine kinase-associated receptors
• The G-protein-coupled receptors
• Singal transduction pathway using cGMP as second
  messenger

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Tyrosine Kinase-associated Receptors

• Ras signal transduction pathway
• Ras a protein exits in all eukaryotic cells
• There are no small molecular weight second
  messengers in this pathwayall of the components
  are proteins
• Ras was discovered as the oncogenic protein coded
  for by the rat sarcoma virus
• Phosphatidylinositide 3-kinase pathway
• JAK/STAT protein-associated receptor

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The Ras Singal Transduction Pathway

• Raf, MEK and ERK mitogen-activated protein
  kinases (MAP) kinases
• Raf rat sarcoma MAPKKK
• MEK Map kinase/ERK MAPKK
• ERK extracellular siganl-regulated protien
  kinase MAPK

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The Ras Singal Transduction Pathway
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The Control of The Ras Protein
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A Rapid Molecular Switch Mechanism
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Multiple Signal Pathways Of The Ras Type
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Phosphatidylinositide 3-kinase Pathway

• PI 3 kinase involved in
• Cell proliferation
• Differentiation
• Other cellular activities including metabolic
  control
• Insulin

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Simplified Insulin Singalling Pathway
IRS insulin receptor substrate PKB protein
kinase B
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Production of The Second Messenger
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JAK/STAT Protein-associated Receptor

• Interferons
• A protective proteins released by cells infected
  by virus
• STAT proteins
• Singal transducer and activator of transcription
• SH2 domains bind to the phosphorylated receptors
• JAK kinase
• Janus kinase
• Has two catalytic sites

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The Singalling Pathway by Which g-interferon
Activates Specific Gene Transcription
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Outline

• Introduction
• What are the singalling molecules
• Intracellular receptor-mediated responses
• Membrane receptor-mediated singalling systems
• Tyrosine kinase-associated receptors
• The G-protein-coupled receptors
• Singal transduction pathway using cGMP as second
  messenger

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The G-protein-coupled Receptors

• G protein
• Heterotrimeric
• A protein made up of three different subunits a,
  b, g
• G protein receptor have no enzymic activity

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The Structure of The b2-adrenergic Recptor
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cAMP
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The Control of Adenylate Cyclase Activity by a
Hormone Such As Epinephrine
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The b2-adrenergic Recptor Function

• PKA protein kinase A
• CREB cAMP response element binding protein
• CRE cAMP response element of gene promoter

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Hydrolysis of Phosphatidylinositol-4,
5-bisphosphate
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The Phosphatidylinositol Cascade
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Phorbol Esters
Tumor-promoting effect
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Structure of a Rod Cell
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The Structures of Light Singal Molecules
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The G-protein-coupled Receptor Involved In Vision
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Simplified Diagram of The Visual Process
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Outline

• Introduction
• What are the singalling molecules
• Intracellular receptor-mediated responses
• Membrane receptor-mediated singalling systems
• Tyrosine kinase-associated receptors
• The G-protein-coupled receptors
• Singal transduction pathway using cGMP as second
  messenger

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Formation of 3,5cyclic GMP
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Production of The Second Messenger cGMP by Two
Routes
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Simplified Summary Diagram of The Singal
Transduction Pathways
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Ch28 Virus and Viroids

• Yuki Juan

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Virus

• Much smaller
• It generates no energy and catalyses no reactions
• Structure simple
• Genetic materials DNA or RNA
• Protein
• ?????
• ?????
• ???????

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How Are Virus Get Into Cells ?

• The receptor-mediated endocytosis

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Bacterial Virus (Bacteriophages)
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Types of Genetic Material in Different Virus

• Double-stranded DNA
• Single-stranded DNA
• Double-stranded RNA
• Single-stranded RNA
• ()sense RNA
• (-)non-sense RNA

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Why can some virues get away with having RNA as
genetic material

• That viral genomes are exceeding small
• therefore the chances of deleterious mutations
  during replication of viral RNA are smaller.
• Rapid mutation helps the virus to escape
  immunological attack by the animal host.

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Double-stranded DNA Viruses

• Transcribed by host RNA polymerase

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Double-strand RNA Viruses

• RNA-dependent RNA polymerases
• Translation by the host cell machinery

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Single-stranded RNA Viruses

• ()sense RNA (HIV)
• The protein synthesizing machinery of the cell
  can immediately translate it into proteins
• (-)non-sense RNA
• An additional RNA-replicating enzyme is needed

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Release of Viral Particles
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Vaccinia

• Double-stranded DNA viruses
• Own RNApolymerase

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Polioviurs

• Naked virion it has only a nucleocapsid shell of
  coat protein but no membrane)
• ()single-strand RNA
• Producing an RNA replicase
• Polyprotein a single largeprotein

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Influenza virus

• (-) strand RNA virus

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Retrovirus
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Bacteriophage lambda