1. Chapter 15
Cellular Signal Transduction
The biochemistry and molecular
biology department of CMU

2. When environment changes:
Monad——responds directly.
Multicellular organisms——signal
through elaborate system of
intercellular or intracellular
communication ， and consequently
regulate functions of organisms.

3. Signaling molecule
Receptor of target cell
Signal
transduction
Intracellular molecule
biological effect

5. §1 Signaling Molecules

6. Signaling molecules
• Signaling molecules, which are
released by signal-producing cells,
reach and transfer biological signals
to their target cells to initiate specific
cellular responses.

7. • Extracellular molecules
• Intracellular molecules

8. 1. Extracellular molecules
protein & peptides: Hormone, cytokine
AA & its derivatives: Gly, Glu,
adrenaline, thyroxine
Steroid: Sex Hormone,
glucocorticosteroid
Fatty acid derivatives: prostaglandin

9. (1) Paracrine signaling
(local chemical mediators)
• Secreted by common cells.
• Reach neighboring target cells by
passive diffusion.
• Time of action is short.
• Such as GF, PG

10. (2) Endocrine signal
• Secreted by endocrine cells.
• Reach target cells by blood
circulation.
• Time of action is long.
• Such as insulin, thyroxine, adrenalin

11. (3) Synaptic signal
(neurotransmitters)
• Secreted by neuronal cells.
• Reach another neuron by synaptic
gap.
• Time of action is short.
• Such as Acetylcholine (Ach),
noradrenaline

12. (4) Gaseous signal
• Simple structure, half life is short
and active in chemistry .
• Such as NO, CO.

13.
GAS MOLECULE

14. (5) Autocrine signal
• Act back to their own cells.
• Such as GF, cytokine, interferon,
interleukin.

15. 2. Intracellular molecule
• Ca2+ ions
• DG, ceramide lipid derivatives
• IP3 carbohydrate
derivatives
• cAMP cGMP nucleotides
• Ras, JAK, Raf proteins

16. Second messenger:
Small molecules synthesized in cells
in response to an external signal are
the second messengers, which are
responsible for intracellular signal
transduction.
Such as Ca2+, DG, Cer, IP3, cAMP,
cGMP

17. Third messengers:
Third messengers are the molecules
which transmit message from outside
to inside of nucleous or from inside to
outside of nucleous, also called DNA
binding protein.

18. Proteins and peptides:
Effect by Hormones, cytokines
membrane Amino acid derivatives:
receptors Catecholamines
Extracellular Fatty acid derivatives:
molecules Prostaglandins
Effect by
Signal intracellular Steroid hormones,
molecules Thyroxine, VD3
receptors
Intracellular cAMP, cGMP, IP3, DG, Ca2+
molecules

19. §2 Receptor

20. Receptor
Receptors are specific membrane
proteins, which are able to recognize
and bind to corresponding ligand
molecules, become activated, and
transduce signal to next signaling
molecules.
Glycoprotein or Lipoprotein

21. ligand
A small molecule that binds
specifically to a larger one; for
example, a hormone is the ligand for
its specific protein receptor.

22. • Membrane receptors
membrane
Glycoprotein
• Intracellular receptors
Cytosol or nuclei
DNA binding protein

23. 1. membrane receptors
(1) Ligand-gate ion channels type
(cyclic receptor)
ligand→receptor→ion channel open or
close

27. (2) G Protein-Coupled Receptors
(serpentine R)
1) 7-helices transmembrane
receptor

28. Oligosaccharide
unit
Cytosolic
side

29. 2) G protein (Guanylate binding
protein)
• G protein refers to any protein which
binds to GDP or GTP and act as signal
transduction.
• G proteins consist of three different
subunits (α, β, γ -subunit).
• α -subunit carries GTPase activity,
binding and hydrolysis of GTP.

31. 3) Classes of G protein
Gs→ α s→AC→cAMP↑
Gi→ α i→AC→cAMP↓
Gq→ α q →PI-PLC→IP3+DAG
Go→ α o→ion channel
Gt→ α t →cGMP PDE→cGMP→
Rhodopsin

33. Glucagon
β-adrenaline →α s →AC↑
ACTH
α-adrenaline
angiotensin Ⅱ
→α i→AC↓
acetylcholine(M2 M4)
GF release inhibitory factor

35. Cholera toxin
Ribosylation of Arg of Gα
ATPase
G α s -ATP Gα s -ADP
AC
cAMP Cl- + H2O Cavity of intestine
HCO3- diarrhea

36. Pertussis toxin
α i -ADP-ribosylation
Gi
AC↑
cAMP ↑
allergy of histamine

37. 4) Effect proteins of G protein
AC
cGMP PDE (phosphodiesterase ）
PLC
PLA2
Channel protein

38. cAMP
ATP

40. 5) Pathway of G protein linked
receptor
H R G protein Es
secondary messeger
Protein kinase
Phophorylation of Es or functional protein
Biological effect

41. (3) Single transmembrane α-helix
receptor
• Tyrosine protein kinase Receptor
(catalytic receptor)
IGF － R, EGF － R
• Non tyrosine protein kinase Receptor
Growth Hormone R, interferon R

43. Tyrosine protein kinase Receptor
or receptor tyrosine kinase (RTK)
Cys-rich
domain
Immunoglobulin
-like
domain
EGFR IGF-1R PDGFR FGFR

44. Insulin
Intracellular
Cytosol insulin effects

45. Non-receptor tyrosine kinase
(NRTK)

46. Domain of Downstream molecules
of TPKR
SH2 domain (Scr homology 2 domain)
SH3 domain
PH domain (pleckstrin homology domain)

48. (4) Guanylate cyclase (GC)
receptor
Membrane receptor –ANP
Soluble receptor – NO, CO

50. 2. Intracellular receptor
(transcription regulated
receptor)
Intracellular R is trans-acting
elememt cis-acting element
gene expression
Localized in the cytosol and/or in
the nucleus.
ligand: Steroid H, VD3, Thyroxine

52. 3. Properties of binding of H
and R
• highly specificity
• highly affinity
• saturation
• reversible binding
• special function model

53. 4. Control of receptor activity
• Phosphorylation or
dephosphorylation of R
• Phospholipid of membrane
• Enzyme catalyzed hydrolysis
• G protein regulation

54. 5. Function of receptor
(1) Recognize the special ligand
(2) Binding to special ligand
(3) Signal transduction
biological effect

55. §3 Pathway of Signal
Transduction

56. Signal transduction mediated
by membrane receptor
• cAMP dependent-protein kinase A
pathway
• cGMP dependent PKG pathway
• Ca2+ dependent PK pathway
• Tyrosine protein Kinase pathway
• NF-κB pathway
• TGF- βpathway

57. 1. cAMP dependent-protein
kinase A pathway
H R
G protein AC cAMP
PKA
Phosphorylation of Es or functional proteins
Biological effects

58. (1) cAMP metabolism
AC PDE
ATP 2+
cAMP 2+ 5'-AMP
Mg Mg
PPi H2O
PDE ： Phosphodiesterase
AC ： Adenylate cyclase

59. NH2
N N
O O O N N
O P O P O P O CH2 O
ATP
O O O H H
H H
OH OH
PPi AC
NH2 NH2
N N N
N
N N O N N
PDE
O CH2 O O P O CH2 O 5'-AMP
cAMP
H H H2O O H H
H H H H
O P O OH OH OH
O

60. (2) Mechanism of cAMP effect
Activate cAMP-dependent
protein kinase (PKA).

62. (3) PKA effect

64. Phosphorylate specifically Ser/
Thr residues in several
proteins
（ 1 ） Regulation of
metabolism
（ 2 ） Regulation of gene
expression

65. hormons: glucagon, epinephrine
active AC inactive AC
ATP phosphorylase b kinase Pi
ATP cAMP
inactive PKA active PKA
P
ADP phosphorylase b kinase H2O
ATP ADP
ATP ADP
P P
glycogen glycogen
synthase phosphorylase b phosphorylase a
synthase
(active) (inactive)
Pi H2O
Pi H2O
protein
phosphatase-1
inhibitor-1 inhibitor-1 P
(inactive) ATP (active)

66. CRE : cAMP response element
(TGACGTCA)
CREB: CRE binding protein

67. CRE DNA
Transcription
mRNA
CREB
CREB
CR
CR
CRE
EB
EB
CR
CREB ＰＰ
B
CREB Ｐ
EB
Ｐ
Ｐ
Ｐ
PKA
PKA
Ｐ
Ｐ

69. 2. Ca2+ dependent PK pathway
(1) Ca2+ -DAG -dependent PKC pathway
PIP2
H R G protein PLC
IP3 DG
ER Ca2+ PS
PKC
Phosphorylation of Es or functional proteins
Biological effects

71. [Ca 2+]i 0.01-1 µmol/L （ 10-7
mol/L ）
[Ca 2+]o 2.5mmol/L （ 10-3 mol/L ）
5000~10000×

72. 1 ） Function of DG and IP3
IP3 + R→open of Ca2 ＋
channel →[Ca2 ＋ ]↑
DG PKC ↑
PS, Ca2 ＋

74. 2 ） Function of PKC
• regulation of metabolism
PKC →Ser/Thr-P of R, enzyme,
Protein of Mb.
• Gene expression

75. Early response:
PKC Trans-acting factor-P
Immediate early genes Third messenger
Late response:
PKC Third messenger-P
Activate genes
Cell proliferation

77. (2) Ca2 ＋ -CaM dependent protein
kinase pathway
H R G protein PLC
IP3
Ca2+ CaM
CaMK
Phosphorylation of Es or functional proteins
Biological effects

78. Calmodulin (CaM ）：
Ca2 ＋ binding protein
4 Ca2 ＋ + CaM → Ca2 ＋ - CaM
↓
CaM kinase↑
↓
Ser/Thr
-P
↓
Ca2 ＋ pump, AC ↑ GC ↑
Es (glycogen synthase, phosphorylase
kinase)

81. 3. cGMP-dependent PKG pathway
ANP
NO, CO
Receptor-
linked GC cGMP Soluble GC
PKG
Phosphorylation of Es or functional proteins
Biological effects

82. (1) cGMP
GC PDE
GTP 2+
cGMP 2+
5'-GMP
Mg Mg
PPi H2O
GC: Guanylate cyclase
(2) Function of PKG
Ser/Thr- P of protein and E

83. ANP （ atrial natriuretic
peptides ）
↓
GC NO
↓
cGMP
↓
PKG
↓
Vascular dilatation

84. peptide hormones neurotransmitters
neurotransmitters AFP hypothalamic pituitrin
G AC GC G PL cell memberane
ATP GTP PIP2(PC)
cAMP cGMP IP3 DG
Ca2+ Ca2+-CaM
PKA PKG PKC
CaM-PK
phosphorylation of enzymes or proteins effects
trans-acting factor P
cis-acting element
nucleus
expression

85. 4. Tyrosine-protein kinase
pathway (TPK)
• TPK receptor is related to
proliferation, differentiation,
dissociation, carcinomatous
change.
• TPK ：
receptor TPK ： Mb.
non receptor TPK ： cytosol

86. (1) Receptor TPK － Ras －
MAPK pathway
• GRB2, SOS, Ras, Raf
• Small G protein: Ras
• MAPK (mitogen-activated protein
kinase) ：
MAPK 、 MAPKK 、 MAPKKK

87. EGF, PDGF
GRB2 － P ϸ
receptor TPK
ÊÜ ÐÍTPK
Ìå Ras － GTP °û
SOS － P
Ĥ
Raf － P
MAPKK － P
nucleus
trans-acting factor － P
MAPK － P
expression

88. (2) JAKs － STAT pathway
ligand
non TPK receptor
JAKs STAT
gene expression

89. • JAKs
• STAT: Signal transductors and
activator of transcription

90. interferons
Plasma membrane
ÖÊĤ
JAK
P£- £- P
84
P
113 STAT complex
113
91 P 91 84 P
48
inactive STAT
Nuclear membrane
ºËĤ
P
113
P 91 84 P transcription
48
gene
»ùÒò
Interferons response element
¸ÉÈÅ Ó¦´ð Ôª¼þ
ËØ

93. Interferon
Dimerization of Receptor
Autophosphorylation of JAK
Phosphorylation of STAT
Nuclear translocation of STAT
Interferon response element
Expression of gene

94. 5. Nuclear factor-κB pathway

95. 6. TGF-βpathway

96. Intracellular receptor
(DNA transcription regulated
receptor)
• Steroid H, VD3, Thyroxine
• Cytosolic R: glycocorticosteroid H
• Nuclear R: thyroxine, estrogen,
androgen, progesterone

98. Serum binding protein
With bound bormone