Signal Transduction Pathways

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Signal Transduction Pathways
Prepared by Samaneh Rahamooz Haghighi
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Introduction

• Cell-to-cell communication is essential for
  organisms
• In multicellular organisms, cell-to-cell
  communication allows the cells of the body to
  coordinate their activities
• Communication between cells is also essential for
  many unicellular organisms
• Biologists have discovered some universal
  strategies and mechanisms of cellular regulation
• Response is determined by combined effects of
  multiple signals
• The plasma membrane plays a key role in most cell
  signaling
• Pathway similarities suggest that ancestral
  signaling molecules evolved in prokaryotes and
  were modified later in eukaryotes(Alberts et al.,
  2002)
• Signaling systems is similar in plants and
  bacteria (Campbell and Reece, 2008)

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The Evolution of Cell Signaling

• Signaling systems is similar in plants and
  animals
• NO, c AMP, c GMP
• Scientists think that signaling mechanisms first
  evolved in ancient prokaryotes and single-celled
  eukaryotes

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(Campbell and Reece, 2008)
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Communication between yeast cells
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Local and Long-Distance Signaling

• Eukaryotic cells may communicate by direct
  contact
• Animal and plant cells have junctions that
  directly connect the cytoplasm of adjacent cells
• These are called gap junctions (animal cells) and
  plasmodesmata (plant cells)
• The free passage of substances in the cytosol
  from one cell to another is a type of local
  signaling(growth factor)

• Direct cytoplasmic connections
• - gap junctions in animal cells
• - plasmodesmata in plant cells
• -contact of surface molecules (cell-to-cell)
  recognition via receptors

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(Campbell and Reece, 2008)
1- Gap junction 2- Cell-cell recognition 3-
local regulators
Communication between cells by direct contact
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Plasmodesmata in plant cells
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• In many other cases of local signaling,
  messenger molecules are secreted by a signaling
  cell
• These messenger molecules, called local
  regulators, travel only short distances
• One class of these, growth factors, stimulates
  nearby cells to grow and divide
• This type of local signaling in animal cells is
  called paracrine signaling

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Signaling pathway

1. Paracrine
2. Synaptic
3. endocrine

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• In many other cases, cells must share information
  with cells they are not touching
• They use (1) local regulators, messenger
  molecules that travel only short distances

(Alberts et al., 2002)
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Local signaling
Target cell
Secreting cell
Secretory vesicle
Local regulator diffuses through extracellular
fluid.
(a) Paracrine signaling
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• Local regulators nearby cells
• paracrine signaling only includes cells of a
  particular organ
• synaptic signaling between neurons

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neurotransmitter

• Another more specialized type of local signaling
  occurs in the animal nervous system
• This synaptic signaling consists of an electrical
  signal moving along a nerve cell that triggers
  secretion of neurotransmitter molecules
• These diffuse across the space between the nerve
  cell and its target, triggering a response in the
  target cell

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Electrical signal along nerve cell triggers
release of neuro- transmitter.
Local signaling
Neurotransmitter diffuses across synapse.
Target cell is stimulated.
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(b) Synaptic signaling
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• Long distance
• nerve transmission
• endocrine signaling

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• And (2) chemicals called hormones for
  long-distance signaling

• In long-distance signaling, plants and animals
  use chemicals called hormones
• In hormonal signaling in animals (called
  endocrine signaling), specialized cells release
  hormone molecules that travel via the circulatory
  system
• Hormones vary widely in size and shape

(Alberts et al., 2002)
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A Preview

• Earl W. Sutherland discovered how the hormone
  epinephrine acts on cells
• E. W. Sutherland studied the relationship between
  epinephrine presence and activation of glycogen
  phosphorylase enzyme
• Sutherland suggested that cells receiving signals
  undergo three processes
• Reception
• Transduction
• Response

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Generic Pathway

• Reception Chemical message (ligand) docks at
  receptor on cell membrane and changes its shape
• Transduction switching message from chemical
  signal received on cell outside to chemical
  messages on interior of cell
• Response Signal transduction cascade occurs
  until end result is reached

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There are three stages in cell
signaling Reception Transduction Respon
se
EXTRACELLULAR FLUID
CYTOPLASM
Plasma membrane
Transduction
Response
Reception
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Receptor
Activation of cellular response
Relay molecules in a signal transduction pathway
Signaling molecule
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Reception, the Binding of a Signaling Molecule to
a Receptor Protein

• The binding between a signal molecule (ligand)
  and receptor is highly specific
• Ligand binding generally causes a shape change in
  the receptor
• A shape change in a receptor is often the initial
  transduction of the signal
• Many receptors are directly activated by this
  shape change
• Most signal receptors are plasma membrane
  proteins
• Hormones
• NO, CO

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• A signal transduction pathway is a series of
  steps by which a signal on a cells surface is
  converted into a specific cellular response

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Three classes of cell surface receptors

• G-PROTEIN-COUPLED RECEPTORS
• ION-CHANNEL-COUPLED RECEPTORS
• ENZYME-COUPLED RECEPTORS

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How important is the G-protein system?

• Used by hormones, neurotransmitters, sensory
  reception, development.
• Many bacteria produce toxins that interfere with
  G-protein systems
• Up to 60 of medicines influence G-protein
  pathways

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Reception- Example I

• G protein-coupled receptors (GPCRs) are plasma
  membrane receptors that work with the help of a G
  protein
• The G protein acts as an on/off switch If GDP is
  bound to the G protein, the G protein is inactive
• GTP/GDP are chemically very similar to ATP/ADP
  but contain Guanine not Adenine
• G proteins bind to the energy-rich molecule GTP
• Many G proteins are very similar in structure
• GPCR pathways are extremely diverse in function

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• G-protein is embedded within cell membrane has
  three subunits inside the cell
• Ligand binding changes the conformation of the
  GPCR and causes it to release alpha subunit
• Alpha subunit moves to another protein called
  adenylyl cyclase
• Binding causes conformational change which
  activates protein (enzyme)
• Enzyme converts ATP ? cAMP

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G Protein-Coupled Receptor
a subunit has GTPase activity
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Mechanism of G protein coupled reception
Plasma membrane
Inactive enzyme
G protein-coupled receptor
Signaling molecule
Activated receptor
GDP
GDP
GTP
Enzyme
G protein (inactive)
CYTOPLASM
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1
Activated enzyme
GTP
GDP
P
i
Cellular response
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The relay protein is called a G Protein
Membrane receptorsG protein-coupled receptors
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Enzyme-Coupled Receptor

• Extracellular signal binding domain and cytosolic
  domain with enzymic activity

• six known groups of enzyme-coupled receptors
• Tyrosine-kinase receptors
• Tyrosine-kinase-associated receptors
• Histidine-kinase-associated receptors
• Tyrosine-phosphatase receptors
• Serine/threonine-kinase receptors
• Guanylyl cyclase receptors

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Reception- Example II

• Receptor tyrosine kinases are membrane receptors
  that attach phosphates to tyrosines
• Has intra- and extracellular domains, also
  membrane domain
• A receptor tyrosine kinase can trigger multiple
  signal transduction pathways at once
• Kinase is an enzyme that attaches a phosphate to
  a substrate
• Growth factor, ansolin

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(Campbell and Reece, 2008)
Figure Membrane receptorsreceptor tyrosine
kinases
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Ras Protein
GEFs Guanine nucleotide exchange factors GAPs
GTPase-activating proteins
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Signal Transduction

• balance between Phosphorylation and
  dephosphorylation activity
• Phosphorylation occur in serine, threonine or
  tyrosine amino acid
• MAP kinase (mitogen activated protein kinase) is
  a serine/threonine- kinase pathway that activate
  by Ras
• Propagation of cells

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Two-Component Signaling Pathway

• Typically consist of
• 1) a membrane-bound Histidine-kinase that senses
  a specific environmental stimulus
• 2) a response regulator protein that mediates the
  cellular response
• Fungi, plant , bacteria

(Buchanan et al., 2000)
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Hybrid kinase systemBacteri, ETR1
(Buchanan et al., 2000)
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Reception- Example III

• A ligand-gated ion channel receptor acts as a
  gate when the receptor changes shape
• When a signal molecule binds as a ligand to the
  receptor, the gate allows specific ions, such as
  Na or Ca2, through a channel in the receptor

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Ion Channels

• Ligand-gated ion channels are very important in
  the nervous system
• The diffusion of ions through open channels may
  trigger an electric signal

(Campbell and Reece, 2008)
Membrane receptorsion channel receptors
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Signaling transduction

• The molecules that relay a signal from receptor
  to response are mostly proteins
• Like falling dominoes, the receptor activates
  another protein, which activates another, and so
  on, until the protein producing the response is
  activated
• At each step, the signal is transduced into a
  different form, usually a shape change in a
  protein

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Protein Phosphorylation and Dephosphorylation

• Phosphorylation and dephosphorylation are a
  widespread cellular mechanism for regulating
  protein activity
• Protein kinases transfer phosphates from ATP to
  protein, a process called phosphorylation
• The addition of phosphate groups often changes
  the form of a protein from inactive to active

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• Protein phosphatases remove the phosphates from
  proteins, a process called dephosphorylation
• Phosphatases provide a mechanism for turning off
  the signal transduction pathway
• They also make protein kinases available for
  reuse, enabling the cell to respond to the signal
  again

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Phosphorylation cascade
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Growth factor
Reception
Receptor
Phosphorylation cascade
Transduction
CYTOPLASM
Inactive transcription factor
Active transcription factor
Response
DNA
Gene
NUCLEUS
mRNA
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Nuclear response to a signal the activation of a
specific gene by a growth factor
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Small Molecules and Ions as Second Messengers

• The extracellular signal molecule (ligand) that
  binds to the receptor is a pathways first
  messenger
• Second messengers are small, nonprotein,
  water-soluble molecules or ions that spread
  throughout a cell by diffusion
• Cyclic AMP and calcium ions are common second
  messengers

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Second Messengers

• Intracellular signaling molecules produced in
  response to an external stimulus
• cAMP (Campbell and Reece, 2008)
• cGMP
• Ca2
• DAG
• IP3
• Phospholipase C
• STAT Signal Transducer and Activator of
  Transcription
• JAK Janus kinases

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• Cyclic AMP (cAMP) is one of the most widely used
  second messengers
• Adenylyl cyclase, an enzyme in the plasma
  membrane, rapidly converts ATP to cAMP in
  response to a number of extracellular signals
• The immediate effect of cAMP is usually the
  activation of protein kinase A, which then
  phosphorylates a variety of other proteins

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cAMP cyclic adenosine monophosphate
CREB (cyclic AMP response elementbinding
protein) CRE (cAMP response element) PKA (protein
kinase A)
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First messenger (signaling molecule such as
epinephrine)
Adenylyl cyclase
G protein
G protein-coupled receptor
Second messenger
Protein kinase A
Cellular responses
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cAMP as a second messenger in a G protein
signaling pathway
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Disruptions in cell signaling pathways

• Bacterial infections (cholera, anthrax,
  pertussis)
• Animal toxins
• Hormone imbalances (diabetes)
• Cancer
• Plant diseases

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Ca2 CalciumDAG, IP3
PK
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phospholipid-derived molecules
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• Calcium ions also act as second messengers.
• One example is activating an enzyme phospholipase
  C to produce two more messengers which will open
  Ca channels.
• The signal receptor may be a G protein or a
  tyrosine kinase receptor.
• Important in muscle contraction.

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Ip3 receptor
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Calmodulin
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EXTRA- CELLULAR FLUID
Signaling molecule (first messenger)
G protein
DAG
GTP
G protein-coupled receptor
PIP2
Phospholipase C
IP3
(second messenger)
IP3-gated calcium channel
Endoplasmic reticulum (ER)
Various proteins activated
Cellular responses
Ca2
Ca2 (second messenger)
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CYTOSOL
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Cell Responses

• Alteration of metabolism
• Rearrangement of cytoskeleton
• Modulation of gene activity

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Response Regulation of Transcription or
Cytoplasmic Activities

• Ultimately, a signal transduction pathway leads
  to regulation of one or more cellular activities
• The response may occur in the cytoplasm or in the
  nucleus
• Many signaling pathways regulate the synthesis of
  enzymes or other proteins, usually by turning
  genes on or off in the nucleus
• The final activated molecule in the signaling
  pathway may function as a transcription factor

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Signaling Efficiency Scaffolding Proteins and
Signaling Complexes

• Scaffolding proteins are large relay proteins to
  which other relay proteins are attached
• Scaffolding proteins can increase the signal
  transduction efficiency by grouping together
  different proteins involved in the same pathway

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ABA (Absisic acid) signal
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The end of signal
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REFRENCES
1- Alberts, B. Johnson, A. Lewis, J. Raff,
M. Roberts, K. Walter, P. (2002). Molecular
biology of the cell. 4 th edition. New
York and London Garland Science 2-
Buchanan, B. Gruissem, W. Jones, R. (2000).
Biochemistry Molecular Biology of Plants. 5
th edition. American Society of Plant
Physiologists. 3- Faurie, B. Cluzet, S.
Merillon, J. (2009). Implication of
signaling pathways involving calcium,
phosphorylation and active oxygen species in
methyl jasmonate-induced defense responses in
grapevine cell cultures. Journal of
PlantPhysiology .vol166 . 4- Hong-Bo, S.
Wei-Yi, S. and Li-Ye, S. (2008). Advances
of calcium signals involved in plant
anti-drought. C. R. Biologies 331 ,587596. 5-
Cara, B. Giovannoni, J. (2008). Molecular
biology of ethylene during tomato fruit
development and maturation. Plant Science 175
,106113. 6- Nelson, D. Cox, M. (2004).
Lehninger principles of biochemistry. 4th
edition. University of WisconsinMadison. 7-
Campbell, N. Reece, J. (2008). Biology. 8th
edition. ISBN 0-321-54325-4. 8- Kramer, B.
Thines, E. Foster, A. (2009). MAP kinase
signalling pathway components and targets
conserved between the distantly related plant
pathogenic fungi Mycosphaerella graminicola and
Magnaporthe grisea. Fungal Genetics and Biology
46 667681.
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Thank for your attention