Cellular Biology

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Cellular Biology
School of Life Sciences Shaanxi Normal University
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CHAPTER 7 CELL COMMUNICATION
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Transportation (See your text book) 70 energy
of cell will be used for transportation. There
are two types of transproteins
Carrier protein (carrier, permease, transporter)
Channel protein Three types of
transportations
Free diffusion (non-polarized
molecules) Passive transportation
Facilitated
diffusion (polarized molecules)
Co-transportation
Na-K
ATPase (Pump) Automatic transportation Proton
pump
Ca pump
ABC transporter Endocytosis and exocytosis
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Roles of cell communication
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I. Basic concepts Some concepts that are easy to
be confused Now, there are many terms
about cell communication used in cell biology,
especially to the cell biology of tumor. But,
some of them are easy to be confused. I define
them as the follows Cell signaling
Cells release some signal out to some cells else.
Cell communication The signal from a
cell is transmitted to another cell by some
transmitter, and causes a specific reaction.
Cell recognition A cell interacts with
another cell by the signal molecules located on
cell surface, and causes specific response of
another cell. Signal transduction The
signals from out side of cell (Light,
electricity, and molecules) are received by the
receptors located on cell surface, cause the
change of intracellular signal level, and start a
serial responses of cell.
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Signal molecules Signals can be chemical
signals or physical signals. Chemical signal is
much more important than physical signal in cell
biology. Chemical signals include
oligopeptides, proteins, gas molecules (NO?CO),
amino acids, nucleotides, lipids, cholesterol,
and others. The characters of chemical
signals are ? specificity ? efficiency. One or
more molecules can cause a strong response
because the signal transduction system can
enlarge the signal stimulation ? they can be
inactivated after the signal transmission. This
is a protection mechanism that organs obtained
during the evolutionary history. By the
routes of generation and role, the chemical
signal molecules can be sorted as 4 types
hormones, neuron transmitters, local mediated
factors, and gas molecules. By the
solubility, the signal molecules can be sorted as
two types lipid soluble and water soluble
molecules. Lipid soluble signal, such as some
hormone, can be transported into cell directly
passing through the bilayers membrane. Water
soluble signal molecule, such as neuron
transmitters, can not pass through the bilayers
membrane. They have to bind to their receptors
and exchange the signal type, transfer the
information to the intracellular signal (cAMP) or
activate the kinase for receptor to result in
cell responses. So, we call these signal
molecules as primary messenger, and intracellular
signal molecules (cAMP, cGMP, IP3 and DG) as
secondary messenger.
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Ca2 can be named as third messenger
because its signal transmission is depended on
secondary messenger. Secondary messenger
can enlarge the signal function. Receptors
Receptor can selectively bind to its ligand
(Signal molecules). Receptor is glycoprotein
usually composed of two function domains at least
(ligand binding part and activating part). The
features of the interaction between ligand and
receptor are ? specificity ? saturated limit ?
high affinity. By the receptors
location, we can sort receptors as intracellular
receptor and cell surface receptor. Intracellular
receptor receives lipid soluble signal, and cell
surface receptor receives water soluble signal.
The response of cell to a signal depends
on both receptor and cell type. Same signal can
cause different responses on different cells. For
examples, Ach can cause the contraction of
skeleton muscle, inhibit the contraction rate of
heart muscle, and cause the secretion of saliva.
Different signal can cause same responses also.
For examples, both adrenalin and pancreatic
glucagon can enhance the level of blood sugar.
If some signal stimulates cell
consistently, cell can make its receptor obtuse
by the ways as following ? modify and inactivate
receptor. ? move the receptor into inside of cell
(receptor sequestration). ? By endocytosis,
digest receptor with lysosome (receptor
down-regulation).
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Cell surface receptor and intracellular receptor
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Protein Kinase Protein kinase is a type
of phosphate transferase that can transfer the Pi
from ATP to specific amino acid residue to
phosphate and activate protein. The
functions of protein kinase during the signal
transduction include 1. regulate protein
activity by phosphorylation. Some proteins will
be activated by phosphorylation, and some will be
inactivated by this modification. 2. enlarge the
signal responses by the phosphorylation.
Types of protein kinase
Kinases Receivers for Pi
Ser/Thr kinase Hydroxyl of Ser/Thr
Tyr kinase Phenol hydroxyl of Tyr
His/Lys/Arg kinase Imidazole ring, guanidine, e-amin
Cys kinase Sulfydryl
Asp/Glu kinase Acyl
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Communication types among cells There
are three main types for the communication. Commu
nication by gap junction By gap
junction, cells can communicate each other
directly based on connexons that are tubes with a
hydrophilic tunnel at 1.5nm diameter inside.
Connexons allow micromolecules, such as, Ca2,
cAMP passed through, that enhances the same type
and bordered cells to response to the signals
from other cells, such as, electric excitation.
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Gap junction
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The communication by plasma membrane bound
molecules We can call this
communication as cell recognition that means the
interaction between receptors and their ligands.
We can sort the recognitions as the following
types ? The recognition between same type cells
from same species of animals. For examples, cell
can recognize the bordered cells during the
development of embryo. The reactions of blood
transmission and skin transplantation are the
recognition between same type cells from
different resource. ? The recognition between
different cells from same species. For examples,
sperm and ovum, T cell and B cell. ? The
recognition between different cells from
different species. For example, pathogens and
host cells. ? The recognition between same type
cells from different species. This recognition
can be managed under experimental condition.
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Chemical communication Chemical
communication is the indirect communication of
cells. This communication means that cells secret
(signaling) the signal molecules, such as,
hormone, and excite the target cells to regulate
the functions of the target cells. 1.
Endocrine Hormone can regulate the function of
target cells distributed anywhere inside of body
efficiently, systemically, specifically, and
consistently. 2.  Paracrine The signal
molecules secreted by cells can spread to the
neighbored cells to regulate them. For example,
cytokines and gas molecules (NO).
3.  Synapse signaling. 4.  Autocrine
The signaling cell and target cell are same type,
or same one (signaling and targeting itself).
Autocrine exists in cancer cells usually. For
example, Colic cancer cells can secrete gastrin
to mediate the expression of oncogenes (c-myc,
c-fos, ras, p21, and others) for the enhancement
of tumor growth.
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Chemical communication
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The types of chemical communication
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II. The signal transductions mediated by plasma
membrane bound receptors Hydrophilic
signal molecules (neuron transmitters, hormones,
growth factors, and others) can not enter cell
directly, they must combine to the specific
receptors bound on membrane surface to cause cell
responses. The membrane surface bound
receptors can be sorted as three types as the
follows ? Ion-channel-linked receptor ?
G-protein-linked receptor ? Enzyme-linked
receptor. Ion-channel-linked receptor distributes
on excitable cells. G-protein-linked receptor and
enzyme-linked receptor are located on most of
cell types that can work as kinase cascade to
phosphate proteins with a serial phosphorylation
reactions to transfer and enlarge the signal step
by step.
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Three types of membrane surface bound receptors
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Ion-channel-linked receptor
Ion-channel-linked receptor is a ligand-gated
channel receptor distributed on excitable cells,
such as, nerve and muscle cells using neuron
transmitters as signal molecules. Neuron
transmitter can bind to the receptor and change
the structure of the receptor, that leads the ion
channel shut down or opened. The permeability of
the membrane to ion will be changed at this time.
Meanwhile, the chemical signal will be exchanged
as electric signal (depolarization), and the
electric signal (electric excitation) will be
transferred to postsynapse cell For example,
acetylcholine receptor exists as three
structures, they can be opened for 1/1,000,000
second when acetylcholine molecule bind to them.
Ion-channel-linked receptors can be
sorted as positive ion channels (receptors for
acetylcholine, glutamic acid, and 5-TH) and
negative channels (receptors for glycine and
?-aminobutyric acid).
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Ion-channel-linked receptor
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A model structure of the receptor of acetylcholine
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Ion-channel-linked receptor at the junction of
nerve and muscle
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G-protein-linked receptor Trimeric
GTP-binding regulatory protein is called as G
protein located on plasma side of membrane. G
protein is composed of subunit a, ß, and ?. G
protein is a switch during the signal
transduction that can shut down when subunit a
binds to GDP, opened up when subunit a binds to
GTP. Subunit a is of GTPase activity that can
hydrolyze GTP. G-protein-linked receptor
is seven-times-transmembrane protein. The
extracellular part of the receptor recognizes and
bind signal molecule, and intracellular part of
the receptor links to G protein. The
extracellular signal bind to the receptor can
cause the second messenger formed inside cell by
the linked G protein. The receptors for
neuron transmitters, peptide hormones are the
G-protein-linked receptor. The receptors for the
physical and chemical excitations of taste sense
and visual sense are G-protein-linked receptors
too. The signal ways mediated by
G-protein-linked receptor include cAMP signal way
and phosphatidylinositol signal way.
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The molecule switch of G protein
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G-protein-linked receptor is seven-times-transmemb
rane protein
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Three structures of the acetylcholine receptor
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cAMP signal way Extracellular signal
binds to the extracellular part of the
G-protein-linked receptor. By the mediation of G
protein, the intracellular part of the receptor
will form the second messenger, cAMP signal that
is intracellular signal. Components of cAMP
signal ?.    Activating hormone receptor (Rs)
/ inhibiting hormone receptor (Ri). ?.   
Activating regulatory protein (Gs) / inhibiting
regulatory protein (Gi). ?.    Adenylyl cyclase
A glycoprotein (150KD) that passes through the
plasma membrane 12 times. With Mg2 or Mn2,
adenylyl cyclase catalyze ATP into cAMP.
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Mg2 or Mn2
Adenylyl cyclase
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?.    Protein Kinase A (PKA) PKA is composed of
two catalytic subunits and two regulatory
subunits. cAMP binds to regulatory subunits and
releases out the activated catalytic subunits
that can phosphate the serine and threonine
residues of some proteins in cells to change the
activity of them. ?.    cAMP phosphodiesterase
It can degenerate cAMP to form 5-AMP, that stops
signal.
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Protein Kinase A
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Degeneration of cAMP
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The model of Gs regulation When Gs is
inactivated, a subunit is combined with GDP, and
adenylyl cyclase has no activity. When the
ligand, such as hormone, combines to Rs
(extracellular part of receptor), the structure
of receptor (Rs) will be changed and the Gs
binding site will be explored and the
ligand-receptor complex will bind to Gs. The
structure of the Gs a subunit will be changed.
This a subunit rejects GDP and combine GTP to
activate it. Gs will releases out its a, ß, and ?
subunits, and explore the adenylyl cyclase
binding site on a subunit. The explored and GTP
combined a subunit will combine adenylyl cyclase
and activate it. The activated adenylyl cyclase
can cause ATP changed to cAMP. With the GTP
hydrolysis, a subunit will return to original
structure and be separated from adenylyl cyclase.
The activation of adenylyl cyclase will be
stopped. a subunit combine ß and ? subunits. Gs
regulation return back to original. The
cholera enterotoxin can catalyze ADP bind to the
a subunit of Gs, that cause a subunit to lose its
GTPase activity resulting in GTP consistent
combination to the a subunit. The a subunit will
keep activated consistently, and the adenylyl
cyclase will be activated forever. These
pathological changes will lead the Na and water
floated out of cells. The patient will take a
severe diarrhea and dehydration.
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The model of Gs regulation
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The cAMP signal way can be summarized as the
follows Hormone G protein linked
receptor G protein adenylyl cyclase
cAMP cAMP dependent PKA Regulatory protein
for gene transcription The different
cell responses to cAMP signal way with different
speed. For examples, The degeneration of glycogen
to glycose-1-phosphate can be started within 1
second in muscle cells. But, it needs several
hours in some secreting cells because activated
PKA will enter nucleus to phosphorate CRE (cAMP
response element) bound protein and regulate the
expression of relative gene. CRE is the
regulation region of DNA sequence to a gene.
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cAMP signal and glycogen degeneration
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cAMP signal and gene expression
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The model of Gi regulation Gi can
inhibit adenylyl cyclase by the following routes
? combine to the a subunit of adenylyl cyclase
and inhibit the activity of enzyme. ? combine to
the a subunit of free Gs by binding to the
complex of ß, ? subunits complex. As result, the
activation of adenylyl cyclase by a subunit of Gs
will be inhibited. The pertussis toxin
can inhibit the binding of the a subunit of Gi to
GTP, and block the inhibition of adenylyl cyclase
by Ri receptor. So, the development and
pathological syndrome of chin cough are
associated with the inhibition of Gi regulation
way. But, the detailed mechanism about this
inhibition keeps unknown so far.
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The model of Gi regulation
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Phosphotidylinositol signal way In the
phosphotidylinositol signal way, extracellular
signal molecules combine to the G protein linked
receptor on membrane surface, and activate the
phospholipase C (PLC-ß) that hydrolyze
4,5-diphophotidylinositol (PIP2) into
1,4,5triphophotidylinositol (inositol phosphate
3, IP3) and diacyl glycerol (DG) as two second
messengers. Extracellular signals are exchanged
as intracellular signals at this time. We call
the signal system as double messenger system).
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Phosphatidylinositol signal way
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IP3 can combine to the IP3 ligand gate
Ca2 channel to open it, and the Ca2
concentration in cell will be lifted up. The high
Ca2 concentration will activate every Ca2
dependent protein. If you use Ca2 carrier
ionomycin to treat cultured cells, you will get
same result as described above. DG can
activate plasma membrane bound protein kinase C
(PKC). PKC is distributed in cell plasma without
activity usually, but when cell received some
excitation, IP3 will make high Ca2
concentration, then, PKC is translocated onto
plasma membrane inside surface to be activated by
DG. The activated PKC can phosphorate Ser/Thr
residues of proteins causing different cell
exhibited with different response. For examples,
secretion of cell, contraction of muscle,
proliferation and differentiation of cell.
The role of DG can be mimicked by phorbol
ester.
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The roles of IP3 and DG
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Ca2 signal level can be regulated by
calmodulin (CaM). Ca2 bound CaM can activate
CaM-Kinase. So, the response of cell to Ca2 is
depended upon the Ca2 bound proteins and
CaM-Kinases in cell. For example, CaM-Kinase II
is adjacent at the synapse of neuron that is
associated with memory formation. IP3
signal will be dephosphorylized or phosphorylized
as IP2 or IP4 to be stopped. Ca2 will be
exported out from cell by the pumps of Ca2 and
Na-Ca2. DG will be stopped by two
ways 1. DG is phosphorylized as phosphatidic
acid. 2. DG is hydrolyzed as monoesterglycerol.
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The cancellation of Ca2 signal
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Other G protein linked receptors 1.The G
protein in chemical receptor The gas
molecules can combined to the G protein linked
receptor in the chemical receptor and activate
adenylate cyclase to form cAMP, and open
cAMP-gated cation channel to depolarize the
membrane to cause the neuron excitation. This
excitation causes olfaction or taste sense.
2.The G protein in optic receptor
Rhodopsin (Rh) is the G protein linked receptor
in optic receptor complex. Light can change the
structure of Rh and degenerate Rh as retinene and
opsin. The opsin can activate G protein. The
activated G protein can activate cGMP
phosphodiesterase to hydrolyze cGMP in retinal
rod cells. The Na channel will be shut down and
the retinal rod cells will be hyperpolarized,
that causes visual sense. The serial
changes described as above can be shown as the
follows briefly Light signal Rh
activated G protein activated cGMP
phosphodiesterase activated The level of
cGMP decreased Na channel shut down
Concentration of Na in retinal rod cell
fallen down Retinal membrane
hyperpolarized The secretion of neuron
transmitters inhibited visual sense
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Retinal rod cell
G protein linked receptor
G protein in optic receptor
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Enzyme linked receptor Enzyme linked
receptor can be sorted as two types 1. The
receptors are of kinase activity, such as,
peptide growth factors (EGF,PDGF,CSF) receptors.
2. The receptors are not of kinase activity,
and they can link to non-receptor tyrosine
kinase. For example, the super receptor family of
cytokine. The receptors above can be
activated when they combine to their ligands by a
dimerization way. Six types of enzyme
linked receptor were identified so far (Because
they have kinase activity, we call them as
receptor kinase) ? Receptor tyrosine kinase. ?
Receptor linked tyrosine kinase. ? Receptor
tyrosine lipase. ? Receptor Ser/Thr kinase. ?
Receptor guanylate cyclase. ? Receptor linked
histidine kinase. Receptor tyrosine kinase
1. Tyrosine kinase Tyrosine
kinase can be sorted as three types ? Receptor
tyrosine kinase (it is located in membrane as a
transmembrane protein). More than 50 types have
been found in vertebrates. ? Plasma tyrosine
kinase, such as, Src family, Tec family, ZAP70
family, and JAK family. ? Nucleus tyrosine
kinase, such as Abl and Wee. The
extracellular part of receptor tyrosine kinase is
to be bound by ligands (polypeptide or hormones).
Intracellular part is catalytic domain. These
receptors include EGF?PDGF?FGF and others.
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The dimerization and self-phosphorylation of
receptor tyrosine kinase
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Receptor tyrosine kinases
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The recognition domain between signal
molecules A 50 100 mer domains in
signal molecules are homologous each other. These
domains can mediate the signal recognition or be
linked together to form the signal transduction
pathways like computer connections to connect
each parts as Signal transduction network.
The domains include SH2 domain (Src
Homology 2 domain) 100mer. Mediate the
combination of signal and the proteins that
contain phosphate tyrosine. SH3 domain
(Src Homology 3 domain) 50100mer. Mediate the
combination of signal and the proteins that
contain prolines. PH domain (Pleckstrin
Homology domain) 100120mer. Combine to membrane
surface phospholipids (PIP2, PIP3, IP3) to
translocate the PH domain protein to membrane
from plasma.
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Ras signal pathway Receptor tyrosine
kinase (RTK) will be activated after signal
combined, structure dimerized, and molecule
phosphorated by itself. The activated RTK can
activate Ras. Ras is a proto-oncogene family
associated with cancer development. Raf is
another proto-oncogene family. It is Sr/Thr
protein kinase and also called as
mitogen-activated protein kinase (MAPKKK). The N
terminal of Raf can bind to Ras to be activated.
Activated Raf will cause a serial reactions of
protein kinase phosphorylation to take effects on
the growth and differentiation of cells. The
statement above is important to understand tumor
development. RTK-Ras signal pathway (a
serial of activations) can be described briefly
as the follows Ligand RTK
adaptor GEF Ras Raf(MAPKKK)
MAPKK MAPK Activated MAPK enters
nucleus Transcription factors (Elk-1and
others) Enhance proto-oncogenes (c-fos,
c-jun) expression Tumors.
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Ras signal pathway
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The signal transductions mediated by insulin
receptor Insulin receptor is receptor
tyrosine kinase too composed of a subunits and ß
subunits. The ß subunit is of kinase activity by
that the insulin receptor substrates (IRS) can be
phophorated. IRS can activate the proteins
containing SH2 domain, such as,
phosphotidylinositol 3-kinase (PI3K).
PI3K can catalyze phosphotidylinositol (PI) to
form other two PI molecules, PI(3,4)P2 and
PI(3,4,5)P3, as the anchoring sites for the
intracellular signal proteins containing PH
domain, and activate these proteins. The signal
pathways for that include ? Activate
Bruton's tyrosine kinase (BTK) and phospholipase
Cy to lead phosphotidylinositol pathway.
? Activate phosphoinositol dependent kinase
(PKD1). PKD1 activates protein kinase B (PKB).
Activated PKB can phosphorate the BAD protein
that is associated with apoptosis to inhibit BAD
activity for cell survival.
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IRS
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The activation of protein kinase B
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Receptor serine/threonine kinases
Receptor Ser/Thr kinases are transmembrane
receptors, and main ligands for it are the
members of the family of transforming growth
factor-ß (TGF-ß) including TGF-ß1 - TGF-ß5.
TGF-ßs are of complicated bio-functions including
cell proliferation inhibiting, matrix synthesis
enhancing, skeleton growing, and others.
Receptor tyrosine phosphatases Receptor
tyrosine phosphatases are transmembrane receptors
too. They are coworkers for receptor tyrosine
kinases probably to regulate cell cycle. CD45 is
the one of these receptors. Like receptor
tyrosine kinases, receptor tyrosine phosphatases
can be translocated as the cytosol tyrosine
phosphatases with two SH domains, SHP1 and SHP2.
The blood cells of the mouse with SHP1 deficiency
are abnormal. It indicates that cytosol tyrosine
phosphatases are associated with the
differentiation of blood cells.
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Receptor guanylate cyclase Receptor
guanylate cyclase is transmembrane protein too.
Like the receptor enzymes above, receptor
guanylate cyclase is composed of extracellular
part for signal binding and intracellular part
for its catalytic activity. The ligands for it
include atrial natriuretic peptides (ANPs) and
brain natriuretic peptides (BNPs). When the blood
pressure is increased, the atrial muscle cells
secret ANPs to enhance the exportation of water
and Na from kidneys, and the vascular smooth
muscle cells are relaxed, the high blood pressure
will be relieved. Receptor super family of
cytokine Cytokine receptors are tyrosine
kinase associated receptors. IL, IFN, CSF (colony
stimulation factor), GH (growth hormone) and
others are important to the communication of
blood synthesizing stem cells and immune cells.
The signal pathway for that is JAK-STAT or Ras
pathway.
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JAK (just another kinase or janus kinase)
is a family that is not receptor tyrosine kinase
including JAK1, JAK2, JAK3 and TYK1. The
substrate for JAK is STAT (signal transducer and
activator of transcription) with SH2 and SH3
domains. This signal pathway is called as
JAK-STAT pathway. It can be briefly described as
the follows 1. Combination of ligand and
receptor causes dimerization of the receptor.
2. The dimerized receptor activate JAK.
3. The activated JAK phosphorates STAT.
4. The phosphorated STAT is dimerized and
explores its nucleus binding signal. 5.
The STAT dimer enters nucleus and regulates gene
expression.
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JAK-STAT signal pathway
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III. The signal transductions mediated by
intracellular receptors The intracellular
receptors are the gene regulatory proteins that
can be activated by hormones. These receptors can
combine inhibiting proteins, such as Hsp90, to
form complexes that are not activated yet. If
they combine to their ligands, such as cortisol
(hormone from adrenal cortex), the inhibiting
protein will fall off from the complex, and the
receptor will be activated because the DNA
binding site is explored. Steroid
hormones are hydrophobic micromolecules (around
300Da). They can pass through the plasma membrane
and nucleus membrane. The activated receptors can
combine to specific DNA sequences to regulate
gene expression. The combination of receptor and
DNA sequence has been proved. The specific DNA
binding sequence is receptor dependent
transcription enhancer. The gene
activation induced by steroid hormone can be
sorted as two stages ? Activate the primary
reactions of transcription of some special genes
fast. ? The gene products in the primary
reactions activate other genes. The primary
reactions will be enlarged in this step. That is
why we say that steroid hormones have enlarged
and very efficient function to regulate the long
time biological effects, such as cell
differentiation. The mechanism for
regulation by thyroid hormone and estrogen is
same to steroid hormones.
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Intracellular receptors
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IV. Regulable protein degeneration and signal
transduction Many very complicated signal
transductions are involved with the cell
development, cell function, and other life
events. Excepting the signal transduction
pathways described as above, the regulable
protein degeneration pathways are also important
for these life events. These pathways include
Wnt, Hedgehog, Notch, NF-?B, and others. These
pathways can take effects on the differentiation
of adjacent cells, so, they are called as lateral
signaling. Wnt signal pathway Wnt is a
type of secreted glycoproteins. If the oncovirus
is integrated to Wnt, the breast cancer will be
induced. This integration was named as Int1. Wnt
signal pathway can cause the accumulation of
ß-catenin in cell. ß-catenin is a multiple
function protein involved with cell junction to
form adhesion belt, but, the free ß-catenin can
enter nucleus to regulate gene expression. If Wnt
is abnormally expressed or activated, it will
cause tumors.
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the receptor for Wnt is frizzled (Frz), a
transmembrane protein. Activated Frz can activate
the dishevelled (Dsh) in plasma, activated Dsh
can block off the degeneration of ß-catenin to
accumulate ß-catenin in plasma. The accumulated
ß-catenin will enter nucleus to interact with T
cell factor / lymphoid enhancer factor (TCF/LEF)
and regulate the target gene expression. TCF/ LEF
is the transcription factors with bidirectional
regulatory function. Its combination to Groucho
can inhibit gene transcription, but to ß-catenin
inhance gene expression. Wnt can bind to another
receptor, LRP5/6, that is LDL-receptor-related
protein (LRP). We do not know LRP5/6 how to
interact with Frz to activate Dsh so far.
Wnt signal pathway can be briefly described as
the follows Wnt Frz Dsh
Inhibition of degeneration of ß-catenin
ß-catenin accumulation Enter nucleus
TCF/LEF Transcription of some
proto-oncogenes (c-myc?cyclinD1).
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Wnt signal pathway
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Notch signal pathway Notch gene was
firstly found in fruit fly. Its absence can cause
the abnormal wing development. During the embryo
development, when the neuron has been
differentiated out from the precursors of
epithelial tissue, the adjacent cells will be
inhibited to differentiate to the same direction
by the combination of the Notch on neuron
differentiated cell and the Delta (ligand for
Notch) on the adjacent cell surface. This
combination can start the Notch signal pathway.
We call this inhibition as lateral inhibition. If
Notch was mutated, the embryo will die during the
development because too many neurons were
formed. Notch signal pathway is composed
of Notch, Notch ligand, and CSL (some DNA bound
protein). When Notch ligand, such as Delta, is
combined with the Notch on adjacent cells, the
Notch molecule will be cleaved by protease and
release out the ICN (intracellular domain of
Notch) that is of nucleus location signal
function. The ICN will enter nucleus to bind to
CLS and regulate gene expression.
The signal pathway can be described as the
follows Delta Notch
Enzyme cleavage ICN nucleus
CLS-IC Gene transcription.
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Notch signal pathway
h
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Notch gene absence can cause the abnormal wing
development of fruit fly
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Hedgehog signal pathway Hedgehog is
secreted protein combined with cholesterol that
is important for embryo development. If this gene
was mutated, the fruit fly will developed out
many spines on its surface like a hedgehog, that
is why the gene was named as Hedgehog. In
vertebrates, there are three genes to encode
Hedgehog at least. They are Shh (Sonic hedgehog),
Ihh (Indian hedgehog), and Dhh (Desert
hedgehog). Patched (Ptc) and Smoothened
(Smo) are transmembrane proteins that mediate
Hedgehog signal transduction into cell plasma.
Ptc can inhibit Smo when Hedgehog is absent. The
combination of Hedgehog and Ptc can stop the
inhibition of Smo by Ptc, then, the activated Smo
will cause a serial of down stream reactions to
finish the Hedgehog signal transduction.
The transcription factor for Hedgehog signal
pathway is Ci or Gli.
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Hedgehog signal pathway
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NF-?B signal pathway NF-?B is the
transcription factor of Rel family. NF-?B is
involved with the regulation of immunology,
inflammation, and the transcription of the genes
that are associated with cell differentiation. In
the cells of mammalian, there are 5 NF-?B
members of Rel family RelA (P65), RelB, RelC,
NF-?B1(P50), and NF-?B2 (P52). Usually, the dimer
of NF-?B is combined with I?B, an inhibition
protein, to be embedded in plasma. Extracellular
excitation can promote the I?B degeneration and
push NF?B dimer to enter nucleus for the
regulation of gene transcription. The
members of I?B family include I?Ba, I?Bß, I?B?,
I?Bd, I?Be, and Bcl-3. IKK (I?B kinase)
is the key kinase for NF-?B signal transduction.
The extracellular signals, such as TNFa and IL-1,
can activate IKK to cause I?B phosphorylation.
The phosphorated IkB is easy to be degenerated.
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TGFß-Smad signal pathway TGFß is a growth
inhibition factor family. TGFß receptors include
receptor I and II on the membrane. TGFß can
activate its receptor II, then, activated
receptor II activates receptor I. The activated
receptor I can phosphate the Smad-1 in plasma.
The activated Smad-1 forms a dimer with Smad-4,
then the dimer enters nucleus, binds DNA, and
starts transcription. TGFß-Smad
signal pathway is important in the primary stage
of embryo development because it can induce some
specific tissue development. TGFß-Smad signal
pathway is also important in tumor development.
In some cancer tissues, such as colic carcinoma,
the TGFß receptor is absent.
TGFß
Receptor II
Smad 1
Receptor I
Nucleus
Complex of Smad 1 and 4
TGFß-Smad pathway
71
My presentation about the chapter of
cell communication ends here. This chapter is
important for your life scientific career but
complicated to your test of cell biology. So, pay
your attention to this chapter please because
signal transduction is one of the hot research
projects for past decades, and will be so in
future.