Signal Transduction

1
Multicellular Organisms have BIG Communication
Problems
Oi! We need some glucose!
Hey You divide now!!!
Will you PLEASE stop dividing!
Come in 7, your time is up!
2
Chapter 6 Signal Transduction
3
Cell communication.
Cell communication and cell recognition
Cell recognition
Cell signal.
Cell receptor.
Signal Transduction
intercellular receptor signal pathway
Signal pathway
cell surface receptor signal pathway..
Integrin protein pathway
Network signal and signal characteristics
4
(No Transcript)
5
Nobel prizes awarded for research in signal
transduction
2001 L. H. Hartwell, R. T. Hunt, P. M.
Nurse MP key regulators of
the cell cycle 2002 S. Brenner, H. R.
Horvitz, J. E. Sulston MP
Apoptosis
6

• 6.1 cell communication and cell recognition
• 6.1.1 Cell communication
• a Secret chemical signal
• b Contact-depend signal( ????????)
• c Gap junction signal

7
(No Transcript)
8
The Secret chemical Signal
Endocrine signaling signaling molecules act on
target cells distant from their site of synthesis
by cells of endocrine organs Paracrine
signaling signaling molecules released by a
cell only affect target cells in close proximity
Autocrine signaling cells respond to
substances that they themselves release, same
cell type chemical snaptic Neuronal signaling
9
?
10

• 6.1.2 cell recognition
• ?????????????????????,?????????????,??????????????
  ?

Cells selectively bind with intercellular signal
by cell surface receptor,trigger a series of
physiological and biochemical changes , result in
integrated cell effect
11

• Signal transduction
• An extracellular signal can produce a change in
  the intracellular state of the cell without the
  initial signal crossing the membrane.

12

• 6.1.3 Cell signal
• Classify by chemical characteristic
• Hydrophobic signal (????????)can transport
  through cell membrane ,bind with receptor in
  cytoplasm and nucleus to form complex
• Hydrophilic signal, cannot transport through
  cell membrane,bind with cell surface receptor and
  produce second signal ,this process called
  signal transduction
• . Gaseous signal NO

13
(No Transcript)
14
Gaseous signal Nitric Oxide

• In response to a signal from nerve cells,
  endothelial????cells that line blood vessels make
  and release nitric oxide.
• Nitric oxide enters muscle cells in the vessel
  wall causing them to relax and dilate (???)
• Blood flow increases and more oxygen can reach
  organs such as the heart.
• The 1998 Nobel prize was awarded to two U.S.
  scientists for discovering this mechanism.

15

• ?Nitric Oxide and Carbon Monoxide
• ?The nitric oxide (NO) is a major paracrine
• signaling molecule in the nervous, immune, and
• circulatory systems. NO is able to diffuse
  directly
• across the plasma membrane of its target cells.
  The
• molecular basis of NO action, however, is
  distinct
• from that of steroid action rather than binding
  to
• a receptor that regulates transcription, NO
  alters
• the activity of intracellular target enzymes.
• ????????????,?????,????????????????NO?????????????
  ??

16
NO
17
classify by signal location

• Extracellular
• Receptors which have N terminal face outwards and
  C terminal inside the cell.
• When bound to a signal molecule, changes its
  conformation
• Signal molecules are specific to their receptors

18

• Intercellular
• Mostly triggered by the extracellular signal
• Which converts the extracellular into an
  intracellular signal
• Eg. - G protein, GTPase, cAMP, Ca, Kinases,
  phosphatases and many more
• Also called as second messengers

19

• 6.1.4 Second messenger and molecular switch
• Second messenger
• Primitive signal bind with receptor and then
  trigger second messenger ( cAMP,IP3,DG,)

20

• ???????????
• ???????????????????????????,??????????????
• ?????????????????
• ??????????cAMP?DG?IP3?cGMP?Ca2

21

• Molecule switch protein
• Protein kinase phosphorylation let it open ,
• Dephosphorylation let it close
• ProteinGTPactive
• ProteinGDPINactive

22
(No Transcript)
23
Communication by extracellular signals steps
1)Synthesis and release of signaling molecules
by the signaling cell 2) Transport of the signal
to the target cell 3) detection of the signal by
a specific receptor protein 4) And change in
cellular metabolism or gene expression triggered
by the receptor-signaling molecule complex 5)
Removal of the signal, often terminating the
cellular response
24

• 6.2 Cell receptor
• Receptor recognition and selectively bind
  with ligand signal, extracellular siganl change
  into intercellular physical or chemical
  signal,triggered a series of process,result in
  biological effect

Membrane Receptor
intracellular receptor cell
surface receptor Nucleus receptor

Cell receptor
25
Receptors

• Signal molecules that do not enter the cell bind
  to cell-surface receptors.
• Signal molecules that enter the cell bind to
  intracellular receptors.

26
intracellular receptor

• Transmembrane receptors
• That span the thickness of the plasma membrane
• Intracellular domain and extracellular domain
• Signal trasduction/through small molecules (Ca)
  Ion Channels

27
intracellular receptor
28
Three classes of cell-surface receptors

• Ion-channel-linked receptors open an ion channel
  in response to the signal molecule.
• G-protein-linked receptors activate an
  intracellular G-protein that in turn activates
  intracellular enzymes.
• Enzyme-linked receptors directly activate a
  membrane bound enzyme.

29

• Nuclear receptors
• Soluble proteins localised within the cytoplasm
  or the nuceloplasm
• Ligand activated trascription activators
• Hormone regulation
• Steroid receptors (located within cytosol

30
Defining a Receptor

• Specificity a receptor must be able to
  distinguish between often closely-related signals
• High affinity signals are often present in low
  concentrations effective receptors can often
  detect nM to pM concentrations
• Saturability a cell has a finite number of
  receptors and, thus there is a limit to the
  number of ligand molecules a cell can bind

31

• Reversibility ligand-receptor association is
  not covalent as the ligand concentration drops
  the complex can dissociate
• Coupling the receptor transfers a signal from
  ligand to cell

32
Coping with Multiple Signals Receptor
Crosstalk
Suppose a cell receives two signals. Signal A
inhibits proliferation, whilst signal B
stimulates proliferation
A
B
kinase
which phosphorylates and inactivates the
receptor for signal B - result no proliferation
Signal A activates a kinase
33

• If crosstalk only works in one direction (A to
  B) then signal A will be dominant
• If crosstalk works in both directions, the
  outcome will depend on several factors e.g.
• Timing of signal perception
• Relative receptor density
• Relative signal concentration

34

• 6.3 intercellular receptor signal pathway
• ?????????????
• ????????????????????,??????????

35
steroid hormone(????)signal pathway
primary response secondary
response
36

• 6.4 cell surface signal pathway

A Ion-channel-linked receptors open an ion
channel in response to the signal molecule. B
G-protein-linked receptors activate an
intracellular G-protein that in turn activates
intracellular enzymes. C Enzyme-linked receptors
directly activate a membrane bound enzyme.
37
(No Transcript)
38

• A (ion-channel-linked receptor)

Types of ion channel
39
B G protein -linked signal pathway

• 1994 Nobel prize. Discovery of G-protein
  coupled receptors and their role in signal
  transduction
• 43,409 articles in Medline that mention G
  proteins.
• G ? GTP???(open )
• G ? GDP???(close

40

• G-protein sructure
• G-protein-coupled receptors
• C-AMP
• G-protein-linked signal pathway

41
G-protein sructure (G-protein subunits)
42
G-protein subtypes

• inhibition of cAMP production
• inhibition of Ca2 channels
• activation of GIRK K channels

• mediates signalling between GPCRs and RhoA
  (GTPase)
• function under investigation

• increased synthesis of cAMP
• activation of Ca2 and K channels

• activation of PLC? leading to
• activation of PKC (DAG)
• intracellular Ca2 release (IP3)

43

• 1. Basic facts about G proteins
• Each G-protein consists of 3 sub-units, sub-units
  can be together or separated.
• Each G-protein has a binding site that can be
  occupied by either GDP or GTP.
• A G-protein is said to be inactive when it is
  bound to GDP.
• A G-protein is said to be active when it is
  bound to GTP.

44

• Small GTP-binding proteins
• Ras (growth factor signal cascades).
• Rab (vesicle targeting and fusion).
• ARF (forming vesicle coatomer coats).
• Ran (transport of proteins into out of the
  nucleus).
• Rho (regulation of actin cytoskeleton)

45
G-proteins
exterior
cytosol
46
G-protein-coupled receptors
?????
Extracellular
-NH2
e3
e2
-S-S-
e1
TM1
TM2
TM3
TM4
TM5
TM6
TM7
D
R
Y
C2
C1
C3
Cytoplasmic
G??????
COOH-
47
cAMP
ATP ? cAMP PPi
48
Cyclic AMP

• Cyclic-AMP is suited to be a transient signal.
• Synthesis degradation of cAMP are both
  spontaneous, but enzymes are required to
  synthesize these reactions.
• Enzymes that synthesize and degrade cAMP are
  regulated.

49
G-protein-linked signal pathway

• C-1 CAMP signal pathway
• C-2 ?????????(Double messenger pathway)

50
Subunit of cAMP
Rs and Ri GS and Gi CAMP enzyme
51
PKA
GENE EXPRESXSION
52
cAMP activate cAMP-depend PKA
53
protein kinase A transcription factor CREB
(CRE-binding protein) expression of
cAMP-inducible genes.
54
CAMP??????????

• ?????
• ?????????cAMP??,??5'-AMP
• ?????
• ????????????Ri, ????Gi???

55
PIP2-DG pathway
56
PKC

• ?Ca²?????,??????
• ????????????,
• ????????????
• ??????????,PKC??????????????,??????????,PIP2??,???
  Ca²??????,??????????????????,???DG????,?PKC
  ?Ca²???????,????????

57
?
58
?????

• ?DAG?????
• DAG???PIP2??????????, ???????, ?????????
• ??DAG???????,?????(PA),PA????CMP-???,????????????(
  PI)?
• ?DAG ?DAG ???????????, ??????????????????????????

59

• ? Removal of IP3
• ?IP3 hydrolyzation
• ?5???????, ???I(1,4)P2, ??
• ????????5????????????
• ??????????3-??????IP3?????I(1,3,4,5)P4?

60

• ?Ca2???? ?
• ?IP4??????????Ca2 ??, ??????Ca2????????
• ???Ca2???????, ???Ca2-ATP?(??????????),????????
  Ca2,?????Ca2?????????(10-7 M),????CaM-??????,???
  ????,???????

61

• C Enzyme linked receptor

• RTK-RAS pathway
• Other enzyme linked receptor

62
(No Transcript)
63
(No Transcript)
64
(No Transcript)
65
GRF
RASGDP
RASGTP
GAP
66
MAP ???
???? ??

MAPKKK MAP
??????

??
MAPKK
MAP
?????

MAPK MAP??
67

• ?Ras ????????
• ?Ras??????????
• ???
• ?????????Ras?Rafl?MAPKKK
• ?MAPKK (MEK)?MAPK,???????????????????
• ?????EGF????,??????????

68
Ras switch
69
(No Transcript)
70

• SUMMARY Receptor tyrosine kinases (RTKs),
  which bind to peptide/protein hormones, may exist
  as dimers or dimerize during binding to
  ligands. Ligand binding leads to activation of
  the kinase activity of the receptor and
  autophosphorylation of tyrosine residues in its
  cytosolic domain. The activated receptor also can
  phosphorylate other protein substrates. Ras is
  an intracellular GTPase switch protein that acts
  downstream from most RTKs.
• RTKs are linked indirectly to Ras via two
  proteins, GRB2 and Sos

71

• The SH2 domain in GRB2, an adapter protein, binds
  to specific phosphotyrosines in activated RTKs.
  The two SH3 domains in GRB2 then bind Sos, a
  guaninenucleotide exchange factor, thereby
  bringing Sos close to membrane-bound Ras
• Binding of Sos to inactive Ras causes a large
  conformational change that permits release of GDP
  and binding of GTP.
• Normally, Ras activation and the subsequent
  cellular response is induced by ligand binding to
  an RTK.

72

• 6.5 Integrin protein pathway
• ????????????????????,??,?????
• ?????????????????
• ?????????????
• ????????????????

73

• 6.6 Network signal and signal characteristics
• A Basic points of signal transduction
• ??????,?????????
• ????????????????
• ????????????
• ?????????
• ???????????
• ??????

B ???????????
74
interaction of Signal pathway
75

• Signal transduction across the plasma membrane
  can cause a cascade of events that amplify the
  signal and distribute it to influence several
  cell processes in parallel.

76
Why do cells communicate?

• During development, cells differentiate to adopt
  specialized roles.
• Cells need to know whether to live, die, or
  divide.
• Neurotransmission.
• Regulation of metabolism.
• Contraction-expansion.
• Secondary sexual characteristics.

77
(No Transcript)
78
Cell Communication

• Why do cells communicate?
• How are signals transmitted between cells?