Cellular signal transduction

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Chapter 16
Cellular signal transduction
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A general introduction
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When outer environment changes
Unicellular organism
Directly responds to
extraneous signals.
Multicellular transmits the information
by the intercellular complicated signal
transduction system, and regulates the activity
of body.
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Intercellular signal transduction can be
transduced by
directly contact between adjacent cells.
Regulation of metabolism and function of
itself and other cells by means of secreting
chemical substances by cells.
chemical substances which regulate the life
activity of cells signaling substance
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General manner of intercellular signal
transduction
target cell
secretive cell
target cell
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second messengers
signal substance (first messenger)
receptor
effector protein
effector protein
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section 1
signaling substances
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?? Intercellular signaling substance
Definition A general designation of
chemical substances which are secreted by the
cells in order to regulate the life activity of
the target cells.
Chemical character protein, peptide,
amino acid derivatives, steroid hormone, fatty
acid derivatives, NO and so on
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Classification
1?Local chemical medium
Paracrine signal
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characteristics

• Paracrine signal molecules are secreted by
  common cells in vivo

• Paracrine signal molecule do not enter blood
  circulation, but arrive nearby target cells by
  diffusion.

• The effective time is usually short.

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2?Hormones
Endocrine signal
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Characteristics

• endocrine signal molecule are secreted by
  endocrine cells which are specially
  differentiated

• arrive the target cells through the blood
  circulation

• effective time of most of them is longer.

For instance
Insulin, thyroxine, adrenalin and so on.
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3. Neural transmitter
Characteristic

• synapse-secreted signal

• secreted by nerve cell

• arrive to the target cell
• through the synaptic cleft

• effective time is short.

e.g.
acetylcholine?noradrenaline and so on .
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Others
Some intercellular signaling substances can
act on the same cell or on the secreting cells
themselves. They are called autocrine signal.
Some intercellular signaling substances can
transmit information in different bodies, e.g.
Insect sex hormone.
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the pathways of intercellular signaling
substances affect the cellular functions
Type Signal substance Receptor Changes in the cells
Neural transmitter acetylcholine?glutamic acid??amido-butyric acid. membrane receptor Effect on the on-off of ion channel
Growth factor insulin-linked growth factor-1 ?epidermal growth factor ?platelet-derived growth factor. membrane receptor resulting in phosphorylation and dephosphorylation of enzyme protein and function protein, change the metabolism of cell and gene expression.
Hormone protein?polypeptide and amino acid ramification and so on hormone?steroid hormone?thyroxine. Membrane receptor intracellular receptor Ditto. Effect the transcription of genes.

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??Intracellular signaling substance
Definition Chemical substance which is
transmiting cell regulation signals within the
cells .
Chemical property
Inorganic ions Ca2
Derivative of lipid DAG?Cer
Derivative of saccharide IP3
nucleotidecAMP?cGMP
signal protein molecule
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? Secondary messenger
Small molecules which are used to transduce
information within the cells. For
instances Ca2?DAG?IP3?Cer?cAMP?cGMP and so on .
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Section 2 receptor
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? Receptor
Receptors are proteins, anchored in cell
membrane or in the cells, which can recognize
and bind with specific biological active
molecules, and result in biological effect.
? Ligand
biological active molecules which can bind with
receptor are named as ligand.
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Intracellular receptor
The receptors located in the cytosol and nucleus
are all DNA binding proteins.
Membrane receptor
Large number of the receptors located on the
plasma membrane are enchasing glycoprotein ?
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?.Classification, structure and function
of receptors
1. Membrane receptor

• circular receptorthe ion channel
• dependent on the ligand

Acetylcholine receptor
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B. ?-helix receptor with seven transmembrane
fragments serpentine
receptor
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? GTP/GDP binding protein
(G protein)
G protein, which is combined with GTP or GDP,
is a kind of peripheric protein which is located
on the cytosolic face of the plasma membrane. It
is composed of three subunits ?????. G protein
has two conformationsinactive state active
state.
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G protein cycle
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Signal transduction mediated by this receptor
can be reduced to
hormone
receptor
G protein
enzyme
second messenger
Protein kinase
Enzyme or other functional protein
biological effect
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G proteins in the process of the signal
transduction
Type of G protein ?-subunit Function
Gs ?s S timulating AC Gi ?i Inhibiting AC Gq ?q PLC stimulating specifically phosphoinositol Go ?o In brain the main G protein which can regulate the ion channel Transportor Ta Stimulating vision
AC adenylate cyclase
PLC phospholipase C
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C. ?-helix receptor with single transmembrane
fragment
IgG-linked sequence
membrane
TPK
EGF-R
IgG immunoglobulins
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Tyrosine protein kinase-linked receptor
Receptor has the activity of tyrosine protein
kinase after binding with ligand. For instance
insulin receptor ?IGF-R?? epithelium growth
factor ?EGF-R)
Receptor not linked with tyrosine protein kinase
Receptor is linked with tyrosine protein kinase
after binding with ligand so to produce the
activity of TPK. For instance growth hormone
receptor, interferon receptor.
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Autophosphorylation
Some receptors with a single transmembrane
fragment have the activity of catalysis. When
they bind with ligand, they will form a
receptor-dimer. The TPK in each monomer will be
activated, and phosphorylate their counterpart in
dimer. This process is known as
autophosphorylatoin.
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Acting mechanism of EGF
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2. Intracellular receptor
A. Structure of receptor
COOH
NH2
Highly variable domain
DNA binding domain
hormone binding site
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B. Correlated ligand Steroid hormone,
thyroxine and retinoic acid and so on
C. Function Most of intracellular
receptors are trans-acting factors. After binding
to the corresponding ligands, they can bind with
DNA cis-acting elements to regulate gene
transcription.
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? ?acting characteristic of receptor

• High specificity

• High affinity

• Saturability

• Reversibility

• Specifically
• acting mode

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??Regulation of the activity of receptor

• Influence of phosphorylation and
  dephosphorylation
• Influence of metabolism of membrane lipid
• enzymatic hydrolysis
• Regulation of Gprotein

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section 3The pathway of signal transduction
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Signal transduction mediaed intracellular
receptor
Signal transduction mediaed membrane receptor
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1. Signal transduction mediated by membrane
receptor

• The pathway of cAMP-protein kinase

• The pathway of cGMP-protein kinase

The pathway of Ca2-dependent protein kinase

• the pathway of tyrosine protein kinase

• the pathway of nuclear factor ? ?

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A. The pathway of signal transduction mediated
by cAMP-protein kinase A
a?constituents
Extracellular signaling molecules(mainly are
glucagon?adrenalin and adrenotrophin).
Receptor,G protein,AC,cAMP , PKA
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b. Synthesis and degradation of cAMP
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(Adenylate cyclase, AC)
(Phosphodiesterase, PDE)
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C.Acting mechanism of cAMP

4cAMP

• Activates of cAMP protein kinase
• Ccatalytic subunit R regulation
  subunit

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(cAMP-dependent protein kinase,PKA)
Serine/threonine protein kinases family
Rregulation subunit Ccatalytic subunit
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D.Effect of PKA
(a) regulation on metabolism
realize the regulation by phosphorylating the
effector proteins.
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Effection of Adrenalin on the metabolism of
glycogen
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Phosphorylation of substrate protein by PKA
substrate results of physilologocal phosphorylation significance
histone lose repression promote transcription on transcription and synthesis of protein ribosome promote promote the synthesis Protein translation of protein membrane change of conformation change of permeability protein and function of membrane ion channel tubulin change of conformation influence the secretion and function function of cells myogen of eacy to bind with Ca2 enhance the contraction cardiac muscle cardiac muscle
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(b)Regulation effect on gene expression
In transcription regulatory region of the genes
regulated by cAMP, there is a consensus
sequenc(TGACGTCA)which is known as cAMP response
element (CRE). cAMP response element binding
protein (CREB) can interact with CRE to regulate
the transcription of the gene.
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(?)the pathway of Ca2-dependent protein kinase

• The pathway of Ca2-phospholipid
• dependent protein kinase

(1) Second messenger DAG,IP3
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The production of DAG,IP3
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lecithin
phosphatidic acid
phosphatidic acid hydrolase
Regulation of metabolism
Gene expression
Ca2-DAG-PKC pathway
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Function of DAG,IP3
DAG DAG, phosphatidylserine and Ca2
cooperate to activate PKC by allosteric effect.
IP3 bind to the receptor on endoplasmic
reticulum so to promote the release of Ca2.
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(2) Structure and function of PKC
Structure and typing
There are four conservative regions of amino
acid sequence (C1, C2, C3, C4 ) and variable
regions(V),dividing into regulation region and
catalytic region.
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Cys-rich DAG binding site and TPA binding site
C1
regulation region
C2
Ca2 binding site
C3
ATP binding site
catalytic region
C4
substrate binding, site of transfer of phosphate
group
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Ca2-dependent type?,?,?
classification
Ca2 non-dependent type ?????????
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The function of physiology of PKC
? Regulating metabolism
The activated PKC cause a series of
phosphorylation of Ser, Thr residues of target
proteins.
Target proteins include
Membrane receptors, Membrane proteins and
various enzymes.
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? Regulation on gene expression
The activation of genes by PKC include early
response and late response.

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2. The pathway of Ca2-CaM-dependent protein
kinase
(the pathway of Ca2-CaM kinase )

• (1) constituents
• receptor, G protein, PLC, IP3,
  Ca2,
• calmodulin, CaM-kinase

calmodulin (CaM) CaM has four Ca2-binding
sites. CaM and Ca2 work together to activate
CaM-kinase, and phosphorylate many proteins
(Ser/Thr residues).
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??The pathway of cGMP-protein kinase
1. constituents
Receptor,Guanylate cyclase (GC ) ,cGMP, PKG
2?Synthesis and degradation of cGMP
GC
phosphodiesterase
GTP
cGMP
5'- GMP
Mg2

Ca2 or Mg2
PPi
H2O
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3?function of PKG
Phosphorylate Ser/Thr residues of proteins or
enzymes
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??The pathway of tyrosine protein kinase
( tyrosine protein kinase , TPK )
Classificatoin
Receptor-TPK(on cell membrane) for instance
insulin receptor, growth facter receptor, and
receptors coded by proto-oncogenes (erb-B, kit,
fins etc.)
Non-receptor-TPK(in cytosol) such as JAK and
TPK coded by proto-oncogenes(src, yes, bcr-abl)
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1. Receptor-TPK-ras-MAPK pathway
1?constituents
catalytic receptor, Grb2, SOS , Ras protein,
Raf protein, MAPK system
Grb2 (growth factor receptor bound protein 2)
SH2 domain ( src homology domain 2) SH2 is
the consensus amino acid sequence in some linking
proteins in cells. SH2 domain is homologous to
tyrosine-protein kinase region coded by
proto-oncogene src. This region can recognize
and bind the phosphorylated tyrosine residue.
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Rasproduct of proto-oncogene,similar to G?
subunit of G protein
SOS(son of sevenless) Proline-rich,can bind to
SH3, and promote the conversion of GDP in Ras to
GTP.
Raf proteinhas the activity of Ser/Thr protein
kinase.
MAPK system(mitogen-activated protein kinase)
Include MAPK, MAPK kinase (MAPKK), MAPKK kinase
(MAPKKK),a group of proteins which are both
enzymes and substrates.
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extracellular signal EGF?PDF and so on.
PTK-linked active receptor
Ras-GTP
Cell membrane
GRB2
SOS
dimer
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outside of cell
inside of cell
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dimerization
Cell membrane
cytosol
Activation of PDGF receptor and signal
transduction
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2. The pathway of JAKs-STAT
formnoncatalytic receptorJAKs
signal transducer and transcription
activator (STAT)
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( ?)The pathway of nuclear factor ?B

• nuclear factor- ? B (NF- ?B)

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• Sketch map of activation
• pathway of NF- ?B

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the pathway mainly involves the signal
transduction in the process of body defence
response, tissue damage and stress,
differentiation and apoptosis, and inhibitation
on the growth of tumor.
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??Signal transduction mediated by
intracellular receptor

• Intracellular receptor
• nuclear receptor
• cytosolic receptor
• ligand
• steroid hormone
• thyroxine

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section 4 crosstalking of
signal transduction
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• Member of one signal pathway can join to activate
  or inhibit another signal pathway.
• Two different signal pathway can together effect
  on same effectic proteins or same regulatory
  region of gene to bring into play effection.
• A kind of signal molecule can effect on several
  pathways of signal transduction.

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section 5 signal transduction
and disease
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Familial hypercholesterolemiadeficiency of
LDL receptor
insulin-independent diabetes mellitus decrease
of insulin receptor or deficiency of function
others For instance cholera and pertussis
are related to the abnormality of G protein.
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summary

• Basic concepts
• Signaling substancesclassification,concept
• receptor concept, types,
• characteristics of interaction with
  ligand
• Second messengers
• Important signal transduction pathway