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					         Chapter 5.2

Cell Signalling
5.2.1 cell communication and cell recognition
A Cell communication
Three ways commmunication
   a Secret chemical signal
   b Contact-depend signal( 接触性依赖的通讯)
  c Gap junction signal
 signal transduction systems
                                  Steroid
   hormones       ion channels    hormones

 Seven-spanning G protein-linked receptors

    adenylate cyclase            G proteins
                     cAMP
  antagonists

Agonists

                kinases        phosphatases

                Tyrosine Phosphorylation
       Cell
     Signals
Multiple signals
regulate cell survival.

Additional signals
regulate cell behavior.

An absence of signals
results in cell death
                               The 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
    Endocrine 内分泌




                         旁分泌




Secret chemical signal
• B cell recognition
• 细胞通过其表面受体与胞内信号物质选择性
  结合,导致胞内一系列生理生化变化,最终
  表现为细胞整体的生物学效应
                      Events
• Stimuli
  – Impinge from the outside
    and interact with the cell
    membrane
  – Neurotransmitters
• Responses
  – Depend on the stimuli
  – Signal trasduction
    cascade for activation of
    gene/s.
  – Genetic programs
                                 Signaling is about
                                 communication
                                 between different
                                 groups of cells and
                                 tissues…how one
                                 group of cells informs
                                 another group of cells
                                 what to do.




Signal transduction refers to how the presence of an
extracellular signal can produce a change in the
intracellular state of the cell without the initial signal
crossing the membrane.
Communication by extracellular signals usually involves
six steps:


1) synthesis and
2) release of signaling molecules by the signaling cell
3) transport of the signal to the target cell
4) detection of the signal by a specific receptor protein
5) and change in cellular metabolism or gene expression
triggered by the receptor-signaling molecule complex
 6) removal of the signal, often terminating the cellular
response
C Cell singnal
• Cell signal
• 亲脂性分子(菑类激素;甲状腺素)(与胞
  内受体结合)

• 亲水性信号分子)(与细胞表面受体结合)

• 气体信号分子 NO
Cells constantly communicate with one another,
through direct contact and by chemical
messengers, such as hormones.


                   This communication is cell signaling.
             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.
Nitric oxide binds directly to an
intracellular enzyme causing a rapid
response.
Signal Transduction
Signal molecules move between cells

Growth factors promote survival and
 stimulate cell proliferation.
Acetylcholine is a neurotransmitter.
Thyroid hormone stimulates metabolism.
Nitric oxide relaxes muscle cells in
 vessels.
Adrenaline increases heart contraction.
Testosterone induces secondary male
 sexual characteristics.
              Types of signals
• 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
       Types of signals contd.
• Intracellular
                              Types
• Intercellular                   Endocrine – Travel through
                                  blood
  – Mostly triggered by the       Paracrine – In the visinity
                                  Autocrine – Same cell type
    extracellular signal          Juxtacrine – Along cell
  – Which converts the            membranes

    extracellular into an
    intracellular signal
  – Eg. - G protein,
    GTPase, cAMP, Ca++,
    Kinases, phosphatases
    and many more
  – Also called as second
    messengers
Hormones
Fast and slow responses
        Post induction events
• Amplification
  – life span of the
    receptor – ligand
    complex
• Intracellular signal
  transduction
  – Ca++ activation
  – NO (Nitric Oxide)
D Cell receptor
Receptor:一种能够识别和选择结合某种配体
 (信号)的大分子,通过信号转导(signal
 transduction),将胞外信号转换为胞内物理或
 者化学信号,以启动一系列过程,最终表现
 为生物学效应。
Cell receptor:intracellular receptor
               cell surface receptor
           Types of receptors
• Transmembrane
  receptors
  – That span the thickness
    of the plasma membrane
  – Intracellular domain and
    extracellular domain
  – Signal to concentration
  – Signal
    trasduction/through small
    molecules (Ca++) – Ion
    Channels
  – Cell potential
          Types of receptors
• Nuclear receptors
  – Soluble proteins localised within the
    cytoplasm or the nuceloplasm
  – Ligand activated trascription activators
  – Hormone regulation
  – Steroid receptors (located within cytosol)
     • Apocomplex formation in the absence of
       the steroid (also contains chaperone
       proteins)
  – RXR and Orphan receptors
In general, signaling by cell-surface receptors
  initiates a cascade of biochemical events
  that result changes in the metabolism of
  the cell.
How are signals transmitted into the cell?

Hydrophobic signal molecules such as
 testosterone or gaseous signal
 molecules such as nitric oxide can
 cross the membrane.
Most signal molecules bind to a cell-
 surface receptor protein where the
 information is converted from one
 form to another in a process called
 signal transduction.
                     Three classes of
The Receptor           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.
  Receptors
Signal molecules that
do not enter the cell
bind to cell-surface
receptors.

Signal molecules that
enter the cell bind to
intracellular receptors.
The Response

 Depending on type of cell and stimulus, the
 response might involve:
 1. Change in gene expression.
 2. Alteration of activity of metabolic enzymes.
 3. Reconfiguration of cytoskeleton.
 4. Change in ion permeability.
 5. Secretion of a hormone or protein.
 6. Activation of DNA synthesis.
 7. Death of cell.
   The same signal molecule can induce
different responses in different cell types
• 第二信使与分子开关
Second messenger:第一信使与受体结合后最
  早产生的的信号( cAMP,Cgmp,IP3,DG,)
分子开关蛋白:switch protein:蛋白激酶使之P
  而开启,蛋白磷酸酯酶去P而关闭
GTP结合蛋白:结合GTP活化,结合GDP失
  活
  The
            Examples of Signal
 Second     Transduction
Messenger   Systems
            Ca2+/calmodulin
            adenylate cyclase/cAMP
            NO
            PLC/PKC
            PI/IP3/DAG
            membrane receptors
            G proteins
            steroid hormones
• 5.2.2通过细胞内受体介导的信号传递
  亲脂小分子与细胞内受体结合
  细胞内受体的本质是激素激活的基因调控蛋
  白,构成细胞内受体超家族
5.2.3通过细胞表面受体介导的信号跨膜传递
• 亲水性的信号与细胞表面受体结合


细胞表面受体

A离子通道欧联的受体(ion-channel-linked receptor)

B 酶偶联的受体(enzyme-linked receptor)

C G蛋白欧联的受体(G protein -linked receptor)
Cell-surface receptor categories
   Can be separated into four classes:
   1) G protein-linked receptors
   2) Ion-channel receptors
   3) Receptors lacking intrinsic catalytic activity
   but directly associated with cytosolic protein
   tyrosine kinases
   4) Receptors with intrinsic enzymatic activity
   (RTKs)
A 离子通道偶联的受体
  (ion-channel-linked
  receptor
B 酶偶联的受体(enzyme-linked receptor)
血小板衍生生长因子   成纤维生长因子
• 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 (see Figure 20-31). The activated receptor also can
 phosphorylate other protein substrates.
   Ras is an intracellular GTPase switch protein that acts downstream
 from most RTKs. Like Gsa , Ras cycles between an inactive GDP-
 bound form and active GTP-bound form. Ras cycling requires the
 assistance of two proteins, GEF and GAP, (see Figure 20-22),
 whereas Gsa cycling does not.
  Unlike GPCRs, which interact directly with an associated G protein,
 RTKs are linked indirectly to Ras via two proteins, GRB2 and Sos
 (see Figure 20-23).
• 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 · GDP and activating its
  exchange function.
   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.
  However, in cells that contain a constitutively active Ras,
  the cellular response occurs in the absence of ligand
  binding.
C G蛋白欧联的受体(G protein -linked
 receptor)


C-1 CAMP signal pathway
C-2 磷脂酰肌醇信号通路(Double messenger
pathway)
C-1 CAMP
signal pathway        G proteins
• 1994 Nobel prize. Discovery of G-protein coupled
  receptors and their role in signal transduction. Gilman,
  Alfred G. and Rodbell, Martin.
  http://www.nobel.se/medicine/laureates/1994/index.html
• 43,409 articles in Medline that mention G proteins.
• 1. Basic facts about G proteins
   – Each G-protein consists of 3 sub-units: Ga, Gb, and Gg.
   – These 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.
Small GTP-binding proteins include (roles indicated):
   initiation & elongation factors (protein synthesis).
   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)

All GTP-binding proteins differ in conformation depending
on whether GDP or GTP is present at their nucleotide
binding site.
Generally, GTP binding induces the active state.
                    cAMP
Adenylate Cyclase (Adenylyl Cyclase) catalyzes:
  ATP  cAMP + PPi
The reaction is driven forward by the cleavage of
PPi, catalyzed by Pyrophosphatase: PPi  2 Pi
                Cyclic AMP

Cyclic-AMP is suited to be a   cAMP              NH2
transient signal.
                                                             N
Synthesis & degradation of              N

cAMP are both spontaneous,
                                                 N           N
but enzymes are required to
synthesize these reactions.           H2             O
                                   5' C 4'
                                             H           H    1'
Enzymes that synthesize        O
                                       H 3'              2' H
and degrade cAMP are                 P  O                OH
regulated.                     O
                                       O-
   cyclicAMP (cAMP) pathway
• Up regulation: When a ligand binds to a
  receptor in a cell membrane the effect is that
  – A. the receptor becomes activated
  – B. the nucleotide binding site on the G-protein is
    altered,
  – C. GTP replaces GDP,
  – D. GDP is released,
  – E. and Ga-GTP gets disassociated from GbGg.
  – F. Ga being active triggers the binding of Ga-GTP to a
    membrane bound adenylate cyclase molecule,
     • activating it for production of cyclicAMP (cAMP).
  Cyclic AMP (cAMP) pathway
• Down regulation – when the ligand dissociates
  from the receptor the effects are
  – A. GTP is hydrolyzed by a GTPase activity on Ga
  – B. Ga-GTP becomes Ga-GDP,
  – C. and disassociates from adenylate cyclase
    molecule, making the later inactive.
  – D. Ga then reassociates with GbGg
  – E. CyclicAMP (in the cytoplasm) is then inactivated
    by the enzyme phosphodiesterase, which hydrolyzes
    it to AMP.
G protein activation/inactivation cycle
         hormone
         signal

                                        outside

         GPCR                          plasma
                                      membrane

              a g        g  a         cytosol
                                 AC
             GDP b       b   GTP

          GTP      GDP         ATP cAMP + PPi
2. Hormone binding to a 7-helix receptor (GPCR) causes
a conformational change in the receptor that is
transmitted to the G protein.
The nucleotide-binding site on Ga becomes more
accessible to the cytosol, where [GTP] > [GDP].
Ga releases GDP & binds GTP (GDP-GTP exchange).
Turn off of the signal:
1. Ga hydrolyzes GTP to GDP + Pi. (GTPase).
The presence of GDP on Ga causes it to rebind
to the inhibitory bg complex.
Adenylate Cyclase is no longer activated.
2. Phosphodiesterase catalyzes hydrolysis of
   cAMP  AMP.
Turn off of the signal (cont.):
3. Hormone receptor desensitization occurs.
This process varies with the hormone.
 Some receptors are phosphorylated via G-protein-coupled
  receptor kinases.
 The phosphorylated receptor may then bind to a protein
  arrestin that blocks receptor-G-protein activation and
  promotes removal of the receptor from the membrane by
  clathrin-mediated endocytosis.
4. Protein Phosphatase catalyzes removal by hydrolysis of
phosphates that were attached to proteins via Protein Kinase
A.
Signal amplification is an important feature of
signal cascades:

 One hormone molecule can lead to formation
  of many cAMP molecules.

 Each catalytic subunit of Protein Kinase A
  catalyzes phosphorylation of many proteins
  during the life-time of the cAMP.

View an animation of a G-protein signal cascade.
C-2  磷脂酰肌醇信号通路(Double
 messenger pathway)
• 5.2.4 细胞表面整联蛋白介导的信号传递
• 整联蛋白是细胞表面的跨膜蛋白包括纤连蛋
  白,胶原,和蛋白聚糖
• 粘着斑功能:机械结构功能;信号传递功能
• 细胞表面到细胞核的信号通路
• 细胞表面到细胞质核糖体的信号通路
• 5.2.5 细胞信号传递的基本特征与蛋白激酶
  的网络整合信息
A 细胞信号传递的基本特征
• 多途径多层次,具备收敛和发散特点
• 既有专一性又具备作用机制的相似性
• 信号可以有控制的适度放大
  具备进行适应的特点
  逐渐降低表面受体的数目
  快速钝化受体
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.
B 蛋白激酶的网络整合信息
 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.
      Cell Communication
Why do cells communicate?
How are signals transmitted between
 cells?
How are signals transmitted across cell
 membranes into the cell interior?
How are signals transmitted within a
 cell?
How do signals affect cell function?
What is the relationship between cell
 signaling and cancer?
       Cell signaling and cancer
RAS is an intracellular GTP binding protein that
 is activated by enzyme linked receptors
Activated RAS proteins create a cascade of
 events that can change protein activity and
 gene expression
RAS proteins control cell proliferation, cell
 survival, and cell differentiation
30% of human cancers have mutations in RAS
 genes which are then called oncogenes
                       Review
1. Compare the structures, locations and functions of
preproinsulin and insulin.

2. Outline the events from translation of the preproinsulin
gene to exocytosis of insulin.

3. Describe the mechanisms by which glucose promotes insulin
secretion.

4. Identify the components of insulin secretion that are
defective in type II diabetes mellitus.

				
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