Bio-Membrane and Cell Signaling: EGF Receptor Signaling and Cancer

This report provides a comprehensive overview of Epidermal Growth Factor (EGF) receptor signaling and its critical role in cancer development. It begins with an introduction to the ErbB receptor family, including its members and their ligands, and then delves into the general signal transduction p...Read More

Bio-Membrane and
Cell Signaling
EPIDERMAL GROWTH FACTOR (EGF) RECEPTOR SIGNALING AND CANCER

Table of Contents
Introduction.................................................................................................................................................2
ErbB receptor family and ligands................................................................................................................2
General ErbB receptor signal transduction pathway....................................................................................2
RAS/ERK pathway......................................................................................................................................3
Negative regulation of RAS/ERK pathway.................................................................................................4
PI3/AKT pathway........................................................................................................................................4
Activation of PI3K:.................................................................................................................................4
Formation of PIP3 and activation of AKT:..............................................................................................4
Downstream signaling:............................................................................................................................4
Negative regulation PI3/AKT pathway.......................................................................................................5
JAK/STAT pathway....................................................................................................................................5
Negative regulation of JAK/STAT pathway................................................................................................5
ErbB receptors and cancer...........................................................................................................................5
Cancers due to ErbB receptor mutation.......................................................................................................5
Therapies and treatment...............................................................................................................................6
Monoclonal antibodies:...........................................................................................................................6
Tyrosine kinase inhibitors:......................................................................................................................6
Combination of therapies:........................................................................................................................6
Conclusion...................................................................................................................................................6
References...................................................................................................................................................7
Table of figures:
Figure 1: General signal transduction pathway...........................................................................................3
Figure 2: RAS/ERK pathway.........................................................................................................................3
Figure 3: Activation of PI3K..........................................................................................................................4
Figure 4: Formation of PIP3K and activation of AKT....................................................................................4
Figure 5: Downstream signaling..................................................................................................................4
Figure 6: JAK/STAT pathway........................................................................................................................5
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Introduction
Epidermal growth factor receptor is the best understood of tyrosine kinase receptor family, which
is also known as ErbB receptor family. Activation of domain occurs when growth factor binds to
receptor and as a result autophosphorylation after which intracellular signaling occurs. Many
growth factors including EGF bind to these receptors. MAPK pathway, JAK/STAT pathway and
PI3/AKT pathway; these all are activated by this receptor family. In cancer, deregulation of
receptors occurs due to overexpression or mutation. Due to which signaling increases and as a
result more proliferation occur.
ErbB receptor family and ligands
This receptor family is made of four receptors and specific ligands family binds to them which
are following:
ErbB1:
This receptor binds with TGF-α, epigen, EGF etc.
ErbB2:
This receptor binds with no ligand. Because ErbB2 receptor doesn’t have any domain and this
receptor works by interacting with other receptors.
ErbB3:
This receptor binds with neuregulin 1,2.
ErbB4:
This receptor binds with epigen, tomoregulin and betacellulin.
General ErbB receptor signal transduction pathway
In signal transduction pathway, first of all ligand binds with the receptor, which leads to the
autophosphorylation of receptor. After that adaptor proteins bind to the receptor and form a
signal transduction complex. These adaptor proteins activate a kinase and then that kinase
phosphorylates and activates another kinase. As a result, process such as cell survival,
differentiation and proliferation occur.
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Figure 1: General signal transduction pathway
RAS/ERK pathway
Another name of this pathway is mitogen activated protein kinase (MAPK) pathway. In this
pathway, first of all EGF binds with the receptor and as a result autophosphorylation of receptor
occurs. After that, Grb2 protein binds and this protein phosphorylates and activates SOS. This
activated SOS then activates RAS. RAS then phosphorylates and activates Raf. Activation of
Raf then activates mitogen kinas kinase Mek1/2 after its phosphorylation. After this,
phosphorylation and activation of Erk1/2 (mitogen activated protein kinase) occurs by Mek1/2.
This activation leads to downstream signaling that includes cell survival and proliferation.
Figure 2: RAS/ERK pathway
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Negative regulation of RAS/ERK pathway
RAS/ERK pathway is stopped by dephosphorylating the receptor by phosphatases. PTP1B
dephosphorylates the receptor and as a result signal transduction mechanism does not occurs.
DSP stops this pathway by dephosphorylating MAPK proteins.
PI3/AKT pathway
Phosphatidylinositides phosphorylates by the PI3K, that is from the family of lipid kinase. This
pathway occurs in three major steps which are following:
Activation of PI3K:
First of all, EGF binds with the receptor and as a result
autophosphorylation of receptor occurs. Then, IRS1 binds to the
receptor whose phosphorylation has been occur and serves as binding
and activation site for the PI3K.
Formation of PIP3 and activation of AKT:
During second step, Phosphatidylinositol 3,4,5-triphosphate
forms when the activated PI3K binds to the (phosphatidylinositol
4,5-biphosphate) PIP2 and phosphorylates it. PIP2 is the
component of membrane. After the formation of PIP3, AKT
binds to it and as a result activation of AKT occurs.
Downstream signaling:
This activated AKT binds to the caspase, BAX and FOXO. As a result, different processes that
include proliferation, differentiation and cell survival occur.
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Figure 3: Activation of PI3K
Figure 4: Formation of PIP3K and activation
of AKT
Figure 5: Downstream signaling

Negative regulation PI3/AKT pathway
The lipid phosphatase PTEN is specific for PIP2 and PIP3. This leads to dephosphorylation and
as a result activation of AKT will not occur and this pathway will stop.
JAK/STAT pathway
In this pathway, first of all EGF binds with the receptor and autophosphorylation of receptor
occurs. After this, STAT binds with the phosphorylated receptor. Then this STAT
phosphorylates and activates the other STAT. Their activation then initiates the transcription of
gene. As a result, proliferation and cell survival occurs.
Figure 6: JAK/STAT pathway
Negative regulation of JAK/STAT pathway
SCOS inhibits JAK activation which leads to the stop of JAK/STAT pathway.
ErbB receptors and cancer
It is a disease in which abnormal proliferation occurs due to mutations. There are three reasons
due to which cancer occurs:
 Due to over expression and mutation of ErbB receptor.
 Due to alteration or mutation of downstream signaling.
 Proliferation without any control.
Cancers due to ErbB receptor mutation
 Breast cancer is due to mutation or over expression of ErbB2.
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AKT BAX
caspase
FOXO
Rheb
mTOR
AKT
Rheb
mTOR
S6K
AKT BAX
caspase
FOXO
Rheb
mTOR
AKT
Rheb
mTOR
S6K

 SCCHN is due to over expression of Erbb1.
 Lung cancer is due to over expression of both ErbbB1 and ErbB2.
 Glioblastoma multiforme is due to over expression of ErbB1.
Therapies and treatment
The treatment and therapies for the cancer are following:
Monoclonal antibodies:
The mechanism of action of these is that, they block or stop the process by blocking the
interaction of the receptor and ligand. These monoclonal antibodies perform their functions
either by interacting with immune system or by the removal of antigen. They play important role
by blocking the downstream signaling.
Tyrosine kinase inhibitors:
These inhibitors play important role by binding competitively with the ATP pocket and as result
stop the signaling pathway.
Combination of therapies:
This one is the effective treatment of cancer. In this, both ErbB signaling inhibitor and inhibitors
of ErbB receptor are given to stop the signaling pathway and as a result proliferation doesn’t
occur.
Conclusion
ErbB receptor family plays important role in the performance of different functions that include
proliferation, cell survival and differentiation. The mutation in the signaling leads to the cancer.
Many treatment and therapies are available but resistance is the major issue. Combination of
therapies (ErbB receptor inhibitors and ErbB signaling inhibitors) will be the most effective
treatment in future.
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References:
 https://www.youtube.com/watch?v=ewgLd9N3s-4
 Signal%20Transduction_%20Pathways, %20Mechanisms%20and%20Diseases%20.pdf
 https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4359325/
 https://www.nature.com/articles/s12276-018-0160-8
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