SIGNAL TRANSDUCTION

Protein
Glycoprotein

HOW A GENE SPEAKS and EXPRESS ITSELF/GENE EXPRESSION

Dr. Viliran
SIGNAL TRANSDUCTION/INTRODUCTION
It is a way of cell to cell communication
SIGNAL
TRASDUCTION
from the word transduce
it is the process of converting extracellular signal to
an intracellular response
process of converting one form to another -- one
form of energy to another form of energy
Example: Dr. Viliran communicating to us through
speaking and you as the students, how will you
accept the signal and how are you going to interpret
the signal? Through listening and answering

What is the energy used by Dr. Viliran in

speaking? Sound waves

How are the students able to listen?

Through the organ of corti. Sound
energy is converted to mechanical energy
Signal Transduction is cell signaling or cell talk

CELL SIGNALLING
How do cells receive and respond to signals from their
surroundings?
Prokaryotes(unicellular organism) and unicellular
eukaryotes are largely independent and
autonomous
Multicellular organisms need intercellular
integration and coordination of cell functions by
way of signaling molecules that are secreted or
expressed on the cell surface of one cell and bind to
receptors expressed by other cells.
If there are signaling molecules, there should be
something to accept the signal; and we call these
RECEPTORS expressed by other cells.

With Transcription, you produce a heterogenous nuclear RNA, which

will undergo further processing (splicing, capping, adenylation) then you
have the mature RNA. Then from the nucleus, it goes to the cytoplasm and
mRNA acts as a template for translation and you produce the protein.

Inside the cell, we have here the signaling molecule interacting with the
receptor usually on the cell membrane. This is the first part of the signal
transduction pathways and then binding of the signaling molecule or the
first messenger with the receptor will cause conformational change that
will lead to activation of proteins functioning as Transcription Factors.
Eventually it will stimulate the gene for expression; either synthesis of
different transcription factors or synthesis of proteins that we gave the
cells response to the first messenger. Transcription factors also help in
expression of other genes.

You learned before the importance of the gene which is being expressed
to produce proteins. You produce chemical substances through gene
expression, and the secreting molecule will now communicate with
another cell through interaction with receptors. These cells will produce
a response now converting it into a intracellular response. When it
produces protein it will interact with another cell.
CELL TO CELL COMMUNICATION
Send Signals as Hormones (speak)
Type of Compound/Classification

Steroid (derived from cholesterol)

Peptide, Protein

Amine (derived from amino acids)

NEP, EP
Target

Organ, Tissue, Cell (Another Cell or Same

Cell)
Receive Signals through Receptors (hear)

Signal is received by other cell which needs to be amplified and then it

will have a greater effect. And then Transduction, this will be converted
into a cellular response.
The response can also affect the signaling molecule (Negative Feedback).

BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

Membrane Receptors
They are located OUTSIDE of the cell
Extracellular recognition domain binds hormone
Intramembrane

Channel function
Intracellular

Coupling domain

Enzymatic domain (signal transduction)

Water soluble, hydrophilic signaling molecules
usually interact with these kinds of receptors.
Hydrophobic molecules can directly enter the cell
straight to nucleus

EXAMPLE of AMPLIFICATION in the cAMP SYSTEM

For example here, you have the Messenger-receptor.
A very good example of it is GLUCAGON or EPINEPHRINE
interacting with a receptor.
Then glucagon or epinephrine will activate the enzyme
ADENYL CYCLASE.
And what is the role of adenyl cyclase? It coverts ATP to cyclic
AMP. So there is increased production of cyclic AMP.
And take note the ratio, 1 signaling molecule activating 1
enzyme and that enzyme produces 100 cyclic AMP. Therefore,
it is amplified.
Then once cAMP increases, it activates now the PROTEIN
KINASE. So 1:1
And this activated protein kinase now phosphorylate the main
function of phosphorylate enzyme, phosphorylate other
enzyme 10x, so 10,000 enzymes and then the phosphorylated
enzyme now will act to increase the glucose. (action of
increased glucagon and NEP).
Expect that a molecule or glucagon will produce almost a
million molecule of glucose.
SIGNAL GENERATING CELLS
Epithelial Cells (mostly)
Connective Tissue
Leydig cells
Granulosa cells
Secretory Cells
Neurons
Glandular cells
RECEPTORS (located in cell membrane and inside the nucleus)
There are signals that can pass the cell membrane and then
they work on the nucleus and directly on the DNA
There are signals mainly water soluble, they cannot pass the
membrane, they are only located outside and the membrane
receptor
Cell associated recognition molecule
Provides high degree of discrimination by the target cells
Functional domains/portions:
Recognition Domain
Coupling Domain

(with DNA or another protein)

Enzyme Domain

kinase cascade
Steroid Receptors
Located INSIDE the cell
Recognition domain binds hormone
Coupling domain binds to

specific DNA region

other proteins such as transcription

factors
Activates/Represses gene
transcription

FUNCTIONS/IMPORTANCE of SIGNALING MECHANISM

homeostasis or maintenance of physiological conditions
growth and development
reproduction
mood
memory
energy production, storage and use
metabolic control
behavior
acute response to infection, wounding
production & differentiation of cells (e.g. blood cells)
any biological process
SIGNAL TRANSDUCTION
The process of converting extracellular signals into
cellular responses.
Extracellular signaling molecules (ligands) - substances
synthesized and released by signaling cells and produce a
specific response only in target cells that have receptors
for the signaling molecules
Another term used for signaling molecule is actually a
LIGAND. The concept is ligand interacting with the
receptor and you create several signaling molecules. This
is what we call the second messengers. And a very
popular second messenger is cyclic AMP. The receptor is
the recipient.
You have a series of reaction, amplification and eventually
that signal outside the cell reaches the DNA. And then you
produce a corresponding cellular response

So you have here lipid soluble messenger; since its lipid soluble, the
receptor is directly in the DNA. It can pass through the cell membrane and
the nuclear membrane. And still, you have the response. Again, ligand
interacts with receptor. It could be a protein or glycoprotein.
Receptor a specific protein that specifically binds a
signaling molecule to initiate a response in a target cell
Cell responses :
changes in gene expression

BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

cell morphology
cell movements

Six steps in SIGNAL TRANSDUCTION:

1. You have to synthesize the signaling molecule by the cell.
2. Release of the signaling molecule by the signaling cell
3. transport of the signal to the target cell
4. Signal interacting with the target receptor on the other cell
5. Once you have the ligand (signal) and receptor interaction,
there will change in cellular metabolism, function, or
development triggered by the receptor-signal complex
6. Removal of the signal because it is not a continuous signal
which often terminates the cellular response.
For example, fasting and starvation. Glucagon works
on the liver activating Glycogenolysis. When it
reaches the correct glucose level, you have to
terminate glycogenolysis and gluconeogenesis
especially in prolonged starvation.
TYPES of SIGNALING:
ENDOCRINE SIGNALING
signaling molecules (hormones) act on target cells
distant from their site of synthesis by cells of
endocrine organs
For example, Adrenal Glands. They release cortisol,
and then it acts on the liver. The pancreas releases
insulin, which acts on different cells such as adipose
cell, fat cells, liver.
PARACRINE SIGNALING
the signaling molecules (neurotransmitters)
released by a cell only affect target cells in close
proximity to it
Example: Acetylcholine
AUTOCRINE SIGNALING
cells respond to substances (growth factors) which
they themselves release

TWO GENERAL KINDS of CELL RECEPTORS:

CELL SURFACE RECEPTORS LIGAND

hydrophilic signaling molecules

INTRACELLULAR RECEPTORS LIGAND

Small hydrophobic signaling molecules

Remember that your cell membrane is composed of

two layers of lipid. Hydrophobic signaling molecules
can pass through it.

Again, we have here the secretory cell producing signaling molecule or

ligand interacting with the receptor.

As you can what is being shown here is the specificity of the ligand with
the receptor. It cannot bind to cell B and C because the receptor is not
appropriate. It only binds to Cell A, with the appropriate specific
receptor. It demonstrates the ligand specificity to the receptor.

MEMORIZE!!!!!!! Dr. Viliran said that it will be a part of the

Exam

CLASSIFICATION of HORMONES based on SOLUBILITY and

RECEPTOR LOCATION:
1.

2.

3.

SMALL LIPOPHILIC MOLECULES that diffuse across the

plasma membrane and interact with intracellular receptors
Steroids(cortisol,progesterone,estradiol,testosteron
e), thyroxine and retinoic acid
WATER-SOLUBLE HORMONES with cell-surface receptor
Peptide hormones insulin, growth factors,
glucagon
Small charged molecules epinephrine,histamine
LIPOPHILIC HORMONES WITH CELL SURFACE RECEPTORS
prostaglandins,thromboxane,leukotrienes (inflammatory
mediators that usually act on the cell surface even though they
are lipophilic)

BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

CLASSES of CELL SURFACE RECEPTORS:

1.

2.
3.

4.

G-protein coupled receptors (GTP-binding)

GPCR
Serpentine receptors E
Example: epinephrine,serotonin, angiotensin,
vasopressin, bradykinin and glucagon receptors
Ion channel receptors
Example : Acetylcholine receptor
Tyrosine kinase-linked receptors that lack intrinsic
enzyme activity
Ex: receptors for cytokines, interferons, and growth
factors
Receptors that penetrate the plasma membrane with
intrinsic enzymatic activity
Ex: Tyrosine kinases ( PDGF, insulin ,EGF,FGF)
Tyrosine phosphatases CD45, T cells,macrophages
Guanylate cyclases activin, TGF- receptors
Note: Memorize the examples/receptors and their
corresponding receptors

(A) In the presence of the ligands such as Ach, there is change in the
conformation of the receptor from a closed position, it will then open up.
(B) G-protein linked receptor. GPCR. So this is your G-protein but upon
binding of the ligand, this activates the protein. Example: Glucagon. So
binding of this ligand glucagon to the receptor activates the G-protein.
Once the G-protein is activated, it activates now the enzyme and then the
active enzyme will have an effect on sugar.
(C) Enzyme-linked Receptor. Insulin and the Growth Factors. So without
the ligand, the catalytic domain or the enzyme is inactive. But upon
binding of the ligand for example, insulin, this activates the enzyme.

So you have here the gated ion channel. It opens up with the
ligand/signal binds to it. This is receptor enzyme activity. The
enzyme is activated with the binding of the signal or the ligand.
Serpentine Receptor or G-protein coupled receptor. So binding
of the ligand activates the G-protein which then activates the
enzyme.
Receptor with no intrinsic enzyme activity.
Adhesion Receptor.
Steroid Receptor. It is direct. There are signals that can pass
the membrane and then it acts on the DNA.

FOUR FEATURES of SIGNAL-TRANSDUCING SYSTEMS

a. Specificity
Particular signals specific to a particular receptor
S1 will bind instead of S2
b. Amplification
EP, Glucagon and Glucose
You amplify the signal
c. Desensitization/Adaptation
Negative Feedback inhibition just to control product formation
because if not there will be a lot of response
d. Integration
You can have a lot of signals but it can be integrated
S1 and S2 can be integrated but there is only one response
SECOND MESSENGERS
Binding of ligands to cell surface receptors leads to a shortlived inc. or dec. in the concentration of Intracellular signaling
molecules termed second messengers
3,5 cyclic AMP (cAMP)
3,5 cyclic GMP (cGMP)
1,2 diacylglycerol (DAG)

inositol 1,4,5 triphosphate (IP3)

inositol phospholipid- phosphoinositides

Calcium
\

BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

MAJOR PATHWAYS to GENERATE SECOND MESSENGERS

2.
3.

linked indirectly via other

proteins (other protein in
between)
SMALLER

PROTEIN KINASES
carry out the process of phosphorylation
opposed by the activity of protein phosphatases
ADAPTER PROTEINS
no catalytic activity
contain domains as docking sites for other protein

MAJOR INTRACELLULAR SIGNALING MECHANISMS

cAMP Pathway
Binding of ligand with G-protein coupled receptor
It then activates the G-protein into a coupled receptor
It then activates enzyme adenylate cyclase
Then there is production of cAMP
Calcium Pathway
Ligand-receptor interaction, GPCR because you have the Gprotein.
Activation of the enzyme causing the release of Calcium
Mainly it is phospholipase enzyme that is activated
Release of Calcium
Calcium interacts with protein
Calmodulin

You have here cAMP production will cause phosphorylation of enzyme

phosphorylase kinase. Once phosphorlated, it activates glycogen
phosphorylase. Glycogen is then integrated to glucose.
OTHER INTRACELLULAR SIGNALING PROTEINS in SIGNAL
TRANSDUCTION:
1.

GTPase Switch Proteins GTP-binding proteins that act as

molecular switches in signal transduction pathways
ON when bound to GTP
OFF when bound to GDP
Two classes of GTPase switch proteins:
a. Trimeric G protein

coupled directly to activated

receptors

BIGGER
b. Monomeric Ras and Ras-like proteins

(A) Signaling by Phosphorylation. So you have the ligand. SIGNAL IN,

So its ADP to a diphosphate. So it is phosphorylation, switching the signal
into on position.
(B) Signaling by GTP-Binding Protein. Signal again the ligand, if it is
bound with GDP, OFF. Phosphorylation, so you have one phosphate here,
it is now bound with GTP. ON. SIGNAL OUT.

So you have here, GPP, GPCR. Take note that the G-protein is not yet
bound with your receptor. It is still inactive but upon binding of the
ligand, when the G-protein will be activated, it will now interact with the
receptor. Upon binding of the receptor with the G-protein, it becomes
active, activating the enzyme.
G PROTEINS (guanine nucleotide-binding proteins)
G protein-coupled receptors are transmembrane
receptors. Signal molecules bind to a domain located
outside the cell
G proteins regulate metabolic enzymes, ion channels,
transporters, and other parts of the cell machinery,
controlling transcription, motility, contractility, and
secretion, which in turn regulate systemic functions such
as embryonic development, learning and memory, and
homeostasis

BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

SIGNALING via G-PROTEIN-COUPLED RECEPTORS (GPCR)

G-Proteins GTP-binding proteins
Trimeric proteins ( )
Coupled directly to activated receptors
GTPases convert GTP to GDP + Pi
ACTIVE- when GTP is bound (ON)
INACTIVE when GDP is bound (OFF)
ACTS AS MOLECULAR SWITCH

Once adenylyl cyclase is activated, ATP is converted to cAMP. cAMP now

converts protein kinase. When it is phosphorylated, protein kinase
becomes active phosphorylating other proteins and create cell response.

G-PROTEIN-COUPLED RECEPTOR/SERPENTINE

On the outside, you have here the domain or the signal interacting with
the ligand.
CELLS RESPONSE

So you have here the subunit and the subunit and subunit. Which
subunit has the binding site for GDP and the GTP?
Its the subunit
This is where GTP binds when it is OFF and GDP when it is ON.
The receptor, the G-protein and ligand. Activation then activates the
enzyme and the enzyme will cause these effects.

Binding of the ligand, then conformational change of receptor, exposing

bing site for G-protein. Then GDP dissociates allowing GTP to bind and

BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

this causes the subunit to dissociate from the GS complex. The subunit
will dissociate then it will bind and activate the enzyme adenylate cyclase.
When the enzyme is active, cAMP is produced. And then it will go back to
the original position, GTP is placed because the receptor has GTPase
enzymatic activity. GTPase acts on GTP, converting it back to GDP.

Glucagon bound to receptor, production on cAMP, phosphorylation of

protein kinase, then phosphorylating glycogen phosphorylase, then
glucose is produced.
No glucagon, activate glycogen synthase, promoting glycogenesis. But the
ligand here is glucagon. It is more on the release of glucose from glycogen.

Activate events altering concentrations of intracellular

mediators (SECOND MESSENGERS)
Common second messengers:
cyclic AMP (cAMP)
Ca++
CYCLIC AMP (cAMP)
Second messenger produced from hydrolysis of
pyrophosphate from ATP
Synthesized by Adenylyl Cyclase
Degraded by cAMP phosphodiesterase by acting on
phosphodiester bond and cutting the phosphate to form
5AMP.

We can see here, the communication. The different signals and

production of cAMP, take note that cAMP-dependent protein kinase once
it is activated by cAMP, there are a lot of effects. You can even stimulate
protein synthesis, calcium transport and DNA synthesis. Glycogen
breakdown and lipid breakdown. Microtubule secretion.
PHOSPHOINOSITIDES
Second messengers derived from phosphorylation of inositol
by PI kinase
1. Phosphatidyl inositol (PI)
2. PI 4-phosphate (PIP)
3. PI 4,5-Biphosphate (PIP2)
4. Inositol 1,4,5-triphosphate (PIP3)
Phospholipid Structure
Sugar Alcohol (glycerol)
R1 - Saturated FA
R2 Unsaturated FA
Phosphate
X Alcohol (e.g. Choline, Inositol, etc)
It was mentioned earlier that once you have the ligand-receptor
interaction, you activate an enzyme. In the cAMP pathway, what is the
enzyme acticated? Adenyl cyclase.

CARBOHYDRATE METABOLISM REGULATION by cAMP

cAMP activates glycogen phosphorylase (glygenolysis)
cAMP inhibits glycogen synthase (Glycogenesis)
Insulin inhibits cAMP
Glucagon and Epinephrine activates cAMP
cAMP increases glucose
Insulin promotes glycogenesis

In the PHOSPHOINOSIDTIDES PATHWAY, the enzyme activated is

phospholipase C. And this enzyme, remember in lipid metabolism, what
are the types of phospholipase?
Phospholipase A1, A2, C, B (each one has its own bond to
cleave)
So where does phospholipase C work?
Generating inositol IP3 and di acylglycerol

TWO BRANCHES of INOSITOL PHOSPHOLIPID PATHWAY

Activated Phospholipase C- cleaves PIP2 to generate IP3 and
DAG(diacylglycerol)
IP3 releases Ca++ from ER
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DAG together with bound Ca++ activates C-Kinase C

Kinase phosphorylates cell proteins

The glycerol with the fatty acid and the phosphate here and the inositol.
Phospholipase C acts on this part and you produce a diacylglycerol (DAG),
and you remove the phosphate and inositol group. So you have DAG and
the inositol phosphate.
Phosphorylate it further and it becomes inositol triphosphate. So these
are your second messengers. IP3 (Inositol Phosphate) and DAG
(diacylglycerol).
And you have the same receptor; G-protein coupled receptor
TRIMERIC G. but instead of adenyl cyclase, you activate enzyme
phospholipase C.
So what is the effect of the second messenger?
DAG inactivate C kinase enzyme
Inositol phosphate causes the release of Calcium from ER
Ca is also considered a second messenger

Above shows release of Calcium from ER to cytoplasm. So once it is

released into cytoplasm, being a second messenger, it relays the message.
Ca now interacts with calmodulin. Calmodulin needs Ca to be functional.
Ca binds with calmodulin, then you have the Active Ca-calmodulin
complex and it activates now Calmodulin-dependent protein kinase. So you
will see the response there; phosphorylation of other proteins.
You have the signal here outside then a cascade of reactions; production
of second messenger IP3 which will release Ca, then Ca binds with
calmodulin. Activated calmodulin now phosphorylates other proteins.
SIGNALING by RECEPTORS TYROSINE KINASES (RTK) and RAS
(smaller GTPase protein)
LIGANDS soluble or membrane-bound protein hormones
NDGF, PDGF, FGF,EGF, insulin (hydrophilic)
Binding stimulates the receptors intrinsic protein kinase
activity
Functions:
cell proliferation, differentiation, cell survival and
metabolism

RECEPTOR TYROSINE KINASE (RTK)

Phosphoinositol (IP3)
Once activated, it will cause release of Calcium from
Endoplasmic Reticulum
1,2-Diacylglycerol (DAG)
It will bind to Calcium to activate C-Kinase enzyme
Remember phosphatidyl inositol phospholipid, it has glycerol, with
carbon, 2 Fatty acids, diacylglycerol with the phosphate and the alcohol
group which is inositol.

RAS the GTPase monomeric protein that transduce signals

from RTK
ACTIVE/ON when bound to GTP
INACTIVE/OFF when bound to GDP
Not directly linked to receptor RTK
KEY LINKS of RAS to RTK
GRB2 adapter protein for receptor
SH2 domain- binds to phosphotyrosine residue in
activated receptor
SH3 domains - bind to and activate Sos

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Sos functions as GEF(guanine nucleotide exchange protein)

converts GDP-Ras to GTP-Ras
CYCLING of RAS between ACTIVE and INACTIVE FORMS
1. Guanine Nucleotide Exchange Factor (GEF) facilitates
dissociation of Ras from GDP
2. GTP binds while GEF dissociates yielding active Ras*GTP
3. Hydrolysis of bound GTP to regenerate inactive Ras*GDP
GEF = Guanine nucleotide Exchange factor
GAP = GTPase activating protein

So you have here the GEF and the GAP. GEF promotes the activation of
Ras. GAP is needed for inactivation of Ras.
ACTIVATION of RAS following BINDING of LIGAND to RTK
1. Binding of ligand causes dimerization and
autophosphorylation of tyrosine residues
2. Binding GRB2 and Sos couples receptor to inactive Ras
3. SOS promotes dissociation of GDP from Ras
4. GTP binds and SOS dissociates from active Ras
GRB2 = growth factor receptor binding protein 2
SOS = son of sevenless

MAP KINASES

Mitogen activated protein (MAP) kinases are

serine/threonine-specific protein kinases that respond to
extracellular stimuli
mitogens, osmotic stress, heat shock
proinflammatory cytokines
regulate various cellular activities, such as
gene expression, mitosis, differentiation,
proliferation, and cell survival/apoptosis

BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

SIGNALING by MAP KINASE PATHWAY

1. MAP KINASE serine/threonine kinase
2. Translocates or enters into nucleus to phosphorylate
proteins involved in transcription
It is because Ras is still in the cytoplasm
For this signaling pathway you need to
stimulate gene expression in nucleus
3. Activation of MAP kinase is induced by activated Ras
4. Other proteins involved:
Raf serine/threonine kinase
MEK- a dual-specificity protein kinase

MEK = MAP kinase kinase and ERK

kinase

CASCADE of PROTEIN KINASES

1. Activated Ras binds to N-terminal of Raf
2. Raf binds to and phosphorylates MEK
3. MEK phosphorylates and activates MAP kinase
4. MAP kinase phosphorylates nuclear transcription factors
mediating cellular responses then translation (produce
protein)
SIGNALING from PLASMA MEMBRANE to NUCLEUS
CRE ( cAmp-response element)
cis-acting DNA sequence in genes regulated by cAMP
CREB (CRE-binding protein)
a transcription factor to which CRE binds
CBP/300
a co-activator allowing CREB to stimulate
transcription
CREB links cAMP to TRANSCRIPTION
1. cAMP activates cAmp-dependent protein kinase (cAPK)
2. cAPK translocates to nucleus and phosphorylates CREB
Similar to MAP Kinase
3. CREB interacts with CBP/300
4. CREB-CBP/300 complex binds to and activates transcription of
target genes

MAP KINASES REGULATE TRANSCRIPTION

MAP kinase is activated via RTK-Ras pathway
Translocates to the nucleus and phosphorylates
activators and repressors of transcription

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10

NF-kB

NF-B (nuclear factor kappa-light-chain-enhancer of

activated B cells) is a protein complex that controls the
transcription of DNA
Why is it called NF-Kappa beta? The B cells are included.
Kapag nabasa ang B cells, mainly, signalling
pathways are involved in the immune system.
The B cell. The antibodies.
Eventually you will end up with the
transmission of DNA, mainly that pertains to
the production of antibodies because
antibodies are proteins.
NF-B is found in almost all animal cell types and is
involved in cellular responses to stimuli such as stress,
cytokines, free radicals, ultraviolet irradiation, oxidized
LDL, and bacterial or viral antigens
NF-B plays a key role in regulating the immune
response to infection (kappa light chains are critical
components of immunoglobulins)
Incorrect regulation of NF-B has been linked to cancer,
inflammatory and autoimmune diseases, septic shock,
viral infection, and improper immune development

There are infection (bacterial/viral), free radicals, reactive

oxygen species, or mitogens.
Eto muna, originally in the cytoplasm.
This is the heterodimer NF kappa beta being held by inhibitor kappa beta.
So kung meron ka ng signal, this inhibitor kappa beta will be
phosphorylated and the process is known as UBIQUITINATION. It is one
way of degrading protein.
If this inhibitor kappa beta is now degraded, NF kappa beta will be free
and it will now translocate, going inside the nucleus that will cause
expression of the genes. So there will be transcription and eventually
translation.
So if sa immune system yan, there will be production of antibodies whose
action is targeted to this infection. You increase the immune response
against that signal because there is infection.

NF-kB TRANSCRIPTION FACTOR

A heterodimer Magkapartner. Hetero means they are
different because one sub-unit is 90 kilo Dalton and the
other one is 65 kilodalton (p50 and p65)
In resting cells, found in cytoplasm bound to an inhibitor
I-k So it is not located in the nucleus immediately. And it
is being held and bound to an inhibitor known as
INHIBITOR KAPPA BETA. Bale parang may nakahawak
sa kaniya kaya nasa cytoplasm lang siya. At ang
humahawak sa kanya ay si inhibitor kappa beta.
In response to an extracellular signal, this inhibitor kappa
beta is phosphorylated and degraded. When the inhibitor
kappa beta gets inhibited,
NF kappa beta will now be relased because it is no longer
held in place by inhibitor kappa beta. So once released
from the inhibition of this I-kB, NF kappa beta
translocates into the nucleus, binds to DNA and regulates
transcription. This is a controlled pathway.
But if you have the signal, it will cause
phosphorylation of the inhibitor kappa beta
which will result to degradation of inhibitor
kappa beta release and transfer of NF kappa
beta into the nucleus.
NF-k translocates to nucleus and binds to DNA and
regulates transcription

P50 p65 NF kappa beta, inhibitor kappa beta, stress, bacterial, viral
incfections, cytokines, phosphorylation of the inhibitor kappa beta.
So una, maactivate muna ang inhibitor kappa beta kinase. If the kinase is
activated, IPB will be phosphorylated. If it is phosphorylated, it will be
degraded; and the p50 & p65 will now translocate here causing gene
expression.

11

Given that this is a signal, what is a possible signal for NF kappa beta?

There is activation of you kappa beta kinase, phosphorylation,

degradation, NF kappa beta becomes free then it enters the nucleus; and
then expression. You have now the production of proteins.

BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

So if it is Immunoglobulin G, yun ang naproduce mo,

immunoglobulin G directed against infection.

GLUCOCORTICOIDS
For the treatment of inflammatory and immune diseases
Inhibition of NF-Kappa beta by glucocorticoids
/Mechanisms:
1. Glucocorticoids increase IB mRNA, which leads to
an increase IB protein and more efficient
sequestration of NF- B in the cytoplasm

So if you have numerous inhibitor kappa

beta NF-kB is sequestered in the
cytoplasm. So you cannot produce the
antibodies. If that is autoimmune, you
decrease the production of antibodies,
destroyed on your own tissue.
2. The glucocorticoid receptor competes with NF- B
for binding with coactivators

So inside the nucleus, there is the

presence of DNA, co-activator and NF

kappa beta. Glucocorticoids displaces

3.

NF kappa beta. So if there is no NF-kB, no

gene expression.
The glucocorticoid receptor directly binds to the
p65 subunit of NF- B and inhibits its activation

Remember that you have the p50 and the

p65. So pwedeng mag-attach ang steroids
(glucocorticoids) sa NF-kB, inhibiting its
activation.

JAK-STAT SIGNALLING PATHWAY

JAK Janus Kinase
STAT Signal transducer and activators of Transcription
The JAK-STAT pathway plays a critical role in the
signalling of a wide array of cytokines and growth factors
leading to proliferation, growth, hematopoiesis,immune
response
JAKs, which have tyrosine kinase activity, bind to some
cell surface cytokine receptors, similar to RTK
The binding of the ligand to the receptor triggers
activation of JAKs.
With increased kinase activity, they phosphorylate
tyrosine residues on the receptor and create sites for
interaction with proteins that contain phosphotyrosinebinding SH2 domains
STATs possessing SH2 domains capable of binding these
phosphotyrosine residues are recruited to the receptors,
and are themselves tyrosine-phosphorylated by JAKs
So saka palang sila mag-aattach upon binding
of the ligand. So the same. Phosphorylation by
JAK.
These phosphotyrosines then act as binding sites for SH2
domains of other STATs, mediating their dimerization
Different STATs form hetero- or homodimers
Activated STAT dimers accumulate in the cell nucleus and
activate transcription of their target genes
So again: Ligand phosphorylating your JAK. Then recruitment of STAT.
Phosphorylation also of the STAT. Dimerization of the STAT. And
translocation to the nucleus.
So 3 na ang magtratranslocate sa nucleus.
1. MAP
2. CATK
3. STAT dimer
4. Even the NF kB is entering the nucleus.
What is the receptor for insulin? RTK, RAS

CAMP SYSTEM
Phsophodiesterase increases the level of cAMP.
If we will enter the cell, there are several reactions occurring.
If you have the cAMP activating the kinase, kinase enzyme
works on the different pathways not only gene expression.
Binding of ligand G protein activation enzyme activation
Activation of glycogen phosphorylase and inhibition of
glycogen synthase. So this is GLYCOGENESIS.

BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

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Protein Kinase A will phosphorylate CREB. When CREB is

phosphorylated, it binds with co-activator CDP300 and it
interacts with cAMP response element (cis active DNA
element).
CREB is the binding protein for CRE element.
And then of course, expression, production of RNA,
transcription and translation

Again, what is signal transduction?

Converting a signal into a cellular response.
So this is your trimeric G-protein

PHOSPHATIDYL INOSITOL PATHWAY

Same.
What is the receptor? G-protein
What kind of G-protein? Trimeric G-protein
Binding of the ligand.
Once the G protein is activcated, it activates what enzyme?
Phospholipase C beta.
It acts on phosphotidyl inositol, producing diacylglycerol plus
inositol triphosphate.
What is the effect of Inositol Triphosphate? Release of
calcium from the endoplasmic reticulum
And what is the effect of calcium? Another second
messenger. This is your second messenger, it binds with
Calmodulin. And then once activated, calmodulin has other
effects.
How about diacylglycerol? It activates the protein C kinase
enzyme, phosphorylating also other proteins.
\

RTK RAS pathway

Receptor Tyrosine Kinase
So you have the ligand. An example is growth factor.
You have the intermediate protein because the monomer
GTPase is not directly bound with the receptor.
Unlike in this one, the trimeric G protein is directly bound with
the receptor.
But in the RTK RAS, there are adaptor proteins, the SOS and
GRTP .
So once RAS is activated, RAP, MEK and activation of MAP, and
translocation of MAP kinase, phosphorylation of CREB and
then activating gene transciption.
So pag tiningnan niyo yung cell, marami pang pathways.
Eto lang yung mga namention natin
G protein
RTK
Jak stat
NF Kappa pathway (kasi pwede natin maintegrate
ang signals)

Having a rough day?

Place your hand over your Heart
Feel that?
Thats called PURPOSE.
Youre alive for a reason.
DONT GIVE UP.
The Lord will fight for you; you need only to be still.
Exodus 14:14
GOD BLESS YOU, FUTURE MD
BIOCHEMISTRY B SIGNAL TRANSDUCTION | FEU-NRMF | Dela Rosa, Hannah Maree & Bernabe, Maria Katrina

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