Transcript Document

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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)
Automatic transportation
Co-transportation
Na+-K+ ATPase (Pump)
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 ① specificity; ② efficiency. One or more
molecules can cause a strong response because the signal transduction system can
enlarge the signal stimulation; ③ 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:
① specificity; ② saturated limit; ③ high affinity.
By the receptor’s 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: ① modify and inactivate receptor. ② move the receptor into inside
of cell (receptor sequestration). ③ 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, ε-amin
Cys kinase
Sulfydryl
Asp/Glu kinase
Acyl
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Communication types among cells
There are three main types for the communication.
Communication 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:
① 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. ② The recognition between different cells from same species.
For examples, sperm and ovum, T cell and B cell. ③ The recognition between different
cells from different species. For example, pathogens and host cells. ④ 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: ① Ion-channel-linked receptor; ② G-protein-linked receptor; ③ Enzymelinked receptor. Ion-channel-linked receptor distributes on excitable cells. Gprotein-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 γ－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 α, β, and γ. G
protein is a switch during the signal transduction that can shut down when
subunit α binds to GDP, opened up when subunit α binds to GTP. Subunit α 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 Gprotein-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-timestransmembrane 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:
①. Activating hormone receptor (Rs) / inhibiting hormone receptor (Ri).
②. Activating regulatory protein (Gs) / inhibiting regulatory protein (Gi).
③. 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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④. 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.
⑤. 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, α 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 α subunit will be changed. This α subunit rejects GDP and
combine GTP to activate it. Gs will releases out its α, β, and γ subunits, and
explore the adenylyl cyclase binding site on α subunit. The explored and GTP
combined α subunit will combine adenylyl cyclase and activate it. The activated
adenylyl cyclase can cause ATP changed to cAMP. With the GTP hydrolysis, α
subunit will return to original structure and be separated from adenylyl cyclase.
The activation of adenylyl cyclase will be stopped. α subunit combine β and γ
subunits. Gs regulation return back to original.
The cholera enterotoxin can catalyze ADP bind to the α subunit of Gs, that
cause α subunit to lose its GTPase activity resulting in GTP consistent
combination to the α subunit. The α 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
cyclase cAMP cAMP dependent PKA
transcription
G protein adenylyl
Regulatory protein for gene
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: ① combine to the α
subunit of adenylyl cyclase and inhibit the activity of enzyme. ② combine to the α
subunit of free Gs by binding to the complex of β, γ subunits complex. As result,
the activation of adenylyl cyclase by α subunit of Gs will be inhibited.
The pertussis toxin can inhibit the binding of the α 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-β) that hydrolyze 4,5-diphophotidylinositol (PIP2) into
1,4,5–triphophotidylinositol (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): ① Receptor tyrosine
kinase. ② Receptor linked tyrosine kinase. ③ Receptor tyrosine lipase. ④
Receptor Ser/Thr kinase. ⑤ Receptor guanylate cyclase. ⑥ Receptor linked
histidine kinase.
Receptor tyrosine kinase:
1. Tyrosine kinase:
Tyrosine kinase can be sorted as three types: ① Receptor tyrosine kinase
(it is located in membrane as a transmembrane protein). More than 50 types have
been found in vertebrates. ② Plasma tyrosine kinase, such as, Src family, Tec
family, ZAP70 family, and JAK family. ③ 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
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include EGF、PDGF、FGF and others.
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): 50~100mer. Mediate the
combination of signal and the proteins that contain prolines.
PH domain (Pleckstrin Homology domain): 100~120mer. 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 α subunits and
β subunits. The β 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:
① Activate Bruton's tyrosine kinase (BTK) and phospholipase Cy to lead
phosphotidylinositol pathway.
② 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-β (TGF-β) including
TGF-β1 - TGF-β5. TGF-βs 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 JAKSTAT 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:
① Activate the primary reactions of transcription of some special genes fast. ②
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
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steroid hormones.
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-κB, 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 β-catenin in cell. β-catenin is a multiple
function protein involved with cell junction to form adhesion belt, but, the free βcatenin 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 β-catenin to accumulate β-catenin in plasma. The accumulated βcatenin 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 β-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 β-catenin
β-catenin
accumulation
Enter nucleus
TCF/LEF
Transcription of some protooncogenes (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-κB signal pathway:
NF-κB is the transcription factor of Rel family. NF-κB 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-κB members of Rel family: RelA (P65), RelB, RelC, NF-κB1(P50), and NFκB2 (P52). Usually, the dimer of NF-κB is combined with IκB, an inhibition protein,
to be embedded in plasma. Extracellular excitation can promote the IκB
degeneration and push NF–κB dimer to enter nucleus for the regulation of gene
transcription.
The members of IκB family include IκBα, IκBβ, IκBγ, IκBδ, IκBε, and Bcl-3.
IKK (IκB kinase) is the key kinase for NF-κB signal transduction. The
extracellular signals, such as TNFα and IL-1, can activate IKK to cause IκB
phosphorylation. The phosphorated IkB is easy to be degenerated.
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TGFβ-Smad signal pathway:
TGFβ is a growth inhibition factor family. TGFβ receptors include receptor I
and II on the membrane. TGFβ 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.
TGFβ
Receptor II
Smad 1
Receptor I
Nucleus
Complex of Smad 1 and 4
TGFβ-Smad pathway
TGFβ-Smad signal pathway is important in the primary stage of embryo
development because it can induce some specific tissue development. TGFβSmad signal pathway is also important in tumor development. In some cancer
tissues, such as colic carcinoma, the TGFβ receptor is absent.
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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.
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