Signal transduction

1. Cellular
communication
SIGNAL
TRANSDUCTION

2. Cell survival depends on an
elaborate intercellular
communication network
• Cells sense and send information
(signals)
• Cells communicate with each other
• Cells must sense and respond to changes
in the environment
• To coordinate and regulate virtually all
aspects of cell behavior including:
metabolism, proliferation, survival and
differentiation.

3. SIGNALING MOLECULES
• Molecules that enable cells to receive
information and communicate with
other cells are called signalling
molecules or LIGANDS.
• (“Ligand”- a molecule, or a molecular
group that binds to another chemical
entity to form a larger complex.)

4. What can be a signal?
- Almost anything
• Peptides - insulin,
glucagon...
• Proteins
• Amino acid derivatives -
epinephrine, histamine
• Other small biomolecules
- ATP
• Steroids, prostaglandins
• Gases - Nitric Oxide (NO)
• Photons
• Damaged DNA
• Odorants, tastants

5. 1. Large distances or
Endocrine signaling
Signaling molecules
are called:
“hormones”
•act on target cells
distant from their
site of synthesis
•usually carried
through the
bloodstream
How do signaling molecules reach the cells?

6. 2. Short distances or
Paracrine signaling
• affects target cells within proximity to the
cell that synthesized the molecule
• usually mediated by neurotransmitters and
some growth factors.

7. 3. No distance or
Autocrine signaling
• the signal feeds-back and affects itself
• action of many growth factors
• these compounds generally act on themselves
to regulate proliferation
• seen frequently in tumor cells

8. 4. Contact-dependent
signaling
Example: signaling by T cells in the immune system

9. SIGNAL TRANSDUCTION
• Any process occurring within cells that convert
one kind of signal/stimulus into another type.
• also known as cell signaling - the transmission of
molecular signals from a cell's exterior to its
interior.
• Signals received by cells must be transmitted
effectively into the cell to ensure an appropriate
response. This step is initiated by cell-surface
receptors which triggers a biochemical chain of
events inside the cell, creating a response.

12. SIGNAL TRANSDUCTION
The conversion of a signal from one type to
another. (e.g. chemical to electrical, electrical to second
messenger pathway, extracellular to intracellular)
survive
divide
differentiate
die
The conversion of
signals into cellular
responses.

13. SIGNALING MOLECULES
a.k.a. Ligand / Primary messenger
Can be a hormone, neurotransmitter,
antigen, bacteria, lipid and other
molecules that can interact with a cell
membrane-bound or intracellular
receptors.
-Water soluble / hydrophilic
-Water insoluble / hydrophobic

14. Hormones as signalling molecules
Types of hormones
The chemical nature of a hormone influences
the way it interacts with its target cells.
Based on chemical structure hormones can be
divided into three types.
• steroid hormones
• peptide hormones and protein hormones
• amino acid derivatives

15. Lipid soluble hormone:
Steroid hormones
•Have a lipid base, hence they are
lipophilic and insoluble in water.
•Require a carrier protein for transport
by blood, which has a water base.
•Lipophilic nature allows steroid
hormones to pass through cell
membranes that are phospholipid in
nature.

16. Lipid soluble hormone

17. Amino acid hormones,
Peptide and Protein
hormones
•Are water-soluble hormones and therefore
hydrophilic.
•Require no assistance to travel in the
bloodstream.
•Hydrophilic nature means they are unable to
pass through phospholipid membranes
without assistance.
•Water-soluble hormones require the
presence of cell surface receptor in order to
transmit the signal into the cell.

18. Water soluble hormone
• Can not diffuse through plasma membrane
• Hormone receptors are integral proteins

19. RECEPTORS
For a cell to act on and respond to a
chemical signal, the cell must have a
receptor to receive the ligand.
•the ligand binds to its specific receptor on a
target cell
•this ligand-receptor interaction induces a
conformational or shape-change in the receptor
Once the signalling molecule or ligand has
interacted with the receptor, the information needs
to be processed to produce the appropriate cellular
response.

20. Receptors can be roughly divided into two
major classes: intracellular receptors and
extracellular receptors.
EXTRACELLULAR RECEPTORS
• Extracellular receptors are integral transmembrane
proteins and make up most receptors.
• They span the plasma membrane of the cell, with
one part of the receptor on the outside of the cell
and the other on the inside.
• Signal transduction occurs as a result of a ligand
binding to the outside region of the receptor (the
ligand does not pass through the membrane).

21. Classes of membrane receptors

22. Plasma membrane / Cell surface
Receptors
(for lipid-insoluble messengers)
a. Receptors that themselves function as ion
channels.
b. Receptors that themselves function as
enzymes.
c. Receptors that are bound to and activate
cytoplasmic JAK kinases.
d. Receptors that activate G proteins, which in
turn act upon effector proteins—either ion
channels or enzymes—in the plasma
membrane.

23. G PROTEIN–COUPLED RECEPTOR (GPCR)

24. G-protein coupled receptors
(GPCRs)
e.g. glucagon-, serotonin-, adrenaline/epinephrine-receptors
• GPCRs are involved in a range of
signaling pathways, including light
detection, odorant detection, and
detection of certain hormones and
neurotransmitters

25. INTRACELLULAR RECEPTORS
(for lipid-soluble
messengers)
•Function in the nucleus
as transcription factors
or suppressors to alter
the rate of transcription
of particular genes.

26. Agonists and antagonist
Antagonist - A molecule that competes for
a receptor with a chemical messenger
normally present in the body. The antagonist
binds to the receptor but does not trigger the
cell’s response.
Agonist – A chemical messenger that binds
to a receptor and activates the downstream
signal transduction pathways. It triggers the
cell’s response. E.g. drug that mimics a
normal messenger’s action.

27. Signal Transduction Process

28. WHAT HAPPENS WHEN A LIGAND
BINDS TO A RECEPTOR?
Example: G protein–coupled receptor (GPCR)

29. G proteins
• also known as guanine nucleotide-binding proteins
• a family of proteins that act as molecular switches inside
cells
• involved in transmitting signals from a variety of stimuli
outside a cell to its interior.
• When they are bound to GTP, they are 'on', and, when
they are bound to GDP, they are 'off'.

30. G protein
- Associated with
the receptor.
“heterotrimeric”
- alpha (α) subunit
- Beta (β) subunit
- Gamma (γ) subunit

31. MECHANISM
• GPCR inactive state: when it is bound to a
heterotrimeric G protein complex.
(GDP is bound to the α sub-unit of G protein).
• “OFF”
receptor
G protein
ligand

32. Binding of an agonist to the GPCR results in a conformation
change in the receptor that is transmitted to the bound Gα
subunit of the heterotrimeric G protein.
“ON”
Ligand (agonist)

33. The activated Gα subunit exchanges GTP in
place of GDP.

34. GTP bound to Gα
triggers the dissociation
of Gα subunit from the
G β-γ dimer and from
the receptor.
The dissociated Gα
interact with other
intracellular proteins to
continue the signal
transduction cascade.

35. The freed GPCR is able to
rebind to another heterotrimeric
G protein to form a new
complex that is ready to initiate
another round of signal
transduction.

36. Second messenger system -
cAMP
Adenylate cyclase
pathway:
- the activated G alpha (α)
subunit migrates to an
intracellular protein (ex.
Adenylate cyclase),
binds to and activates
this enzyme, which, in
turn, catalyzes the
conversion of ATP into
cyclic adenosine
monophosphate
αβ
γ
Adenylate cyclase
OR
Adenylyl cyclase

37. Second messenger
systems
Second messengers - are substances that
enter or are generated in the cytoplasm as a
result of receptor activation by the first
messenger.
The second messengers diffuse throughout
the cell to serve as chemical relays from the
plasma membrane to the biochemical
machinery inside the cell.

38. Second messenger system:
GPCR associated with a trimeric
signal-transducing G protein
Ligand binding activates the receptor
Activated receptor  activates
the G protein  which activates
an effector enzyme  to
generate an intracellular second
messenger
– e.g. adenylyl cyclase – converts
ATP to cAMP

39. What do these secondary
messengers do?
It activates a class of
proteins (enzymes)
called
KINASES
Increased concentration of
the second messenger cAMP
may lead to the activation of:
-Ex. protein kinase A (PKA).

40. AND WHAT DO THESE
KINASES DO?
It activates effector proteins that
leads to cellular responses.
Once PKA is activated, it phosphorylates a
number of other proteins including:
•enzymes that convert glycogen into glucose
• enzymes that promote muscle contraction in
the heart leading to an increase in heart rate
• transcription factors, which regulate gene
expression

41. Transmitting the Signal: Protein Kinases
•Activated receptors frequently transmit signals through intracellular
signaling proteins called kinases
•Protein kinases are enzymes that add a phosphate group from ATP
onto a substrate protein; this reaction is called
PHOSPHORYLATION

42. • a variety of protein kinases
are involved in signal
transduction pathways
• involve a series of reactions
(cascade)
• the ultimate phosphorylation
of key proteins underlies the
cell’s biochemical response
to the first messenger.
PROTEIN KINASE
Kinase 1
Kinase 2
Kinase 3
Phosphorylation Cascade
P
P
P

43. The response of a particular cell to a signal
depends on the type of proteins it contains.

44. Adrenaline
signaling
Signal: Adrenaline (epinephrine)
• Secreted by adrenal gland
Receptor: β-adrenergic receptor
Response:
• Breakdown of glycogen to glucose to provide
energy for “fight-or-flight”

45. Insulin
signaling
Signal: insulin
• Secreted by β cells of pancreas
Receptor: a receptor kinase
Response:
• Sugar is taken up from bloodstream into
cells
• Increased cellular uptake of glucose.

46. Action of lipid-soluble hormones
Hormone diffuses
through phospholipid
bilayer & into cell.
Binds to receptor
turning on/off specific
genes.
New mRNA is formed
& directs synthesis of
new proteins.
New protein alters
cell’s activity.

47. Action of water-soluble hormones
Can not diffuse through plasma
membrane
Hormone binds to its receptors - act as
first messenger
Receptor protein activates G-protein in
membrane
G-protein activates adenylate cyclase to
convert ATP to cAMP in the cytosol.
• Cyclic AMP is the 2nd messenger
• Activates kinases in the cytosol to
speed up/slow down physiological
responses
• Phosphodiesterase inactivates cAMP
quickly
• Cell response is turned off unless
new hormone molecules arrive

48. Ion channel receptors
-ligand binding changes the conformation of the receptor so that
specific ions flow through it.
-the resultant ion movement alters the electric potential across
the plasma membrane
-found in high numbers on neuronal plasma membranes
e.g. ligand-gated channels for sodium and potassium
-also found on the plasma membrane of muscle cells
-binding of acetylcholine results in ion movement and eventual
contraction of muscle.

49. Acetylcholine / Ach (neurotransmitter) is released from
motor neuron. Ach binds with receptors in the muscle
membrane opens Na+
Channel to allow sodium to enter.

50. Receptor tyrosine kinases
(RTK) or ligand-triggered
protein kinases
- receptors with intrinsic catalytic activity - ligand binding
activates it and the activated receptor acts as a kinase
- recognize soluble or membrane bound peptide/protein
hormones that act as growth factors (e.g. NGF, PDGF,
insulin)
- binding of the ligand stimulates the receptor’s tyrosine
kinase activity.
Signal
transduction
Cascade

51. Tyrosine kinase-linked receptors
e.g. erythropoietin, interferons
• lack intrinsic catalytic activity
• binding of the ligand results in the formation of a receptor
dimer (2 receptors)
• this dimer then activates a class of protein called tyrosine
kinases
• results in the phosphorylation of downstream targets.

52. CONCLUSIONS:
• Binding of extracellular signalling molecules
to cell surface receptors triggers intracellular
signal transduction pathways that ultimately
modulate cellular metabolism, function, or
gene expression.
• Signals from one cell can act on distant cells
(endocrine), nearby cells or on the same cells.
• G proteins transduce signals from coupled
cell surface receptors to associated effector
proteins, which are either enzymes that form
effector proteins or cation channels protein.

53. • An external signal is amplified downstream from a cell
surface receptor.
• Receptor tyrosine kinases transduce signals via their
associated of intrinsic protein kinases. Ligand
binding triggers the formation of functional dimeric
receptors and phosphorylation of the activation lip in
the kinases, enhancing their catalytic activity.
• Ligand binding leads to activation of intrinsic protein
kinase activity of RTKs and phosphorylation of
tyrosine residues in its cytosolic domain.
• RTKs are linked indirectly to Ras, an intracellular
GTPase switch protein which can activate the MAP
kinase enzymatic cascade, leading to alteration in
gene transcription.

54. References
•Alberts et al. Molecular Biology of the Cell, Chapter 15
•Dohlman, H. and Thorner, J. Regulation of G-Protein initiated signal transduction in
yeast: paradigms and principles. Annu. Rev. Biochem. 2001. 70:703–54
•Bao et al. Pheromone-dependent destruction of the Tec1 transcription factor is
required for MAP kinase signaling specficity in yeast. Cell. 2004. 119: 991
•Schwartz and Madhani. Principles of MAP kinase signaling specificity in
Saccharomyces cerevisiae. Annu. Rev. Genet. 2004. 38: 725
•Park, Zarrinpar and Lim. Rewiring MAP kinase pathways using alternative scaffold
assembly mechanisms. Science 2003. 299:1061
•Mr.M.Pareja (ppt presentation) .. Thanks!