Cancer Cell Signalling

The EGFR-RAS-MAPK Pathway

Dr. Tariq S. H. Al Jabry
Department of Genetics
College of Medicine and Health Sciences (COMHS)

tariqaljabry@squ.edu.om
 Cell-Cell Communication
• All multicellular organisms need to
communicate in order to coordinate actions.

• Coordination is necessary for cells, tissues,

organs, and organ systems to function in
perfect harmony as part of an organism as a
whole.

• Communication between cells must also be

internalised, and this is carried out by cellular
signalling.
Image source: https://www.flickr.com/photos/lynn_el/
 Cell-Cell Communication
• Communication between cells can
be electrical or chemical.

• Structures known as gap junctions

exist between almost all types of
adjacent cells for low-resistance
rapid electrical signalling.

• These structures act as small

channelled pores between cells.

• Allow for the rapid transfer of ions

and small water-soluble molecules.

Berridge, 2014
 Cell-Cell Communication
• Cells can also communicate
using chemical stimuli.

• Stimuli sent out by cells can be

received at target cells via
specific cell surface receptors.

• Receptors can then mediate an

internal signalling cascade
with a resulting biological
response.

Berridge, 2014
 Cell Signalling
• Stimuli acting on cell surface
receptors set off internal
signalling cascades which can
have several components.

• They are usually first

conveyed by transducers that
can be amplified in a
signalling cascade.

• These signals can engage

sensors that are coupled with
effectors to illicit their
biological action.

Berridge, 2014
Cell Signalling

Berridge, 2014
 Cell Signalling: Stimuli
Taste Pore
• Cells are sensitive to an enormous variety of
stimuli.

• Most stimuli are chemical in nature, such as

hormones, neurotransmitters and growth
factors.

• Cells can also detect other modalities such as a

wide range of sensory stimuli (Light, oxygen,
odorants, sound, tastants, touch, temperature).

Berridge, 2014 https://www.d.umn.edu

 Cell Signalling: Stimuli
• Stimuli can be released from cells in different ways.

• Many stimuli are formed within the cytoplasm and

leave the cell by diffusing across the plasma
membrane.

• In some cases, stimuli can be presented to receptors by

specialised molecules.

• A classic example is the role of MHCII on the antigen-

presenting cell that binds fragments of antigen that are
then presented to the T cell receptor.

Berridge, 2014 Deeg, 2014

 Cell Signalling: Stimuli
• A number of stimuli,
particularly growth factors
and cytokines, are carried in
vesicles to the cell surface.
• They appear as a membrane-
anchored cell surface stimuli
that can act precursors that
can be released by proteases.
• ADAM (A Disintegrin And
Metalloproteinase) proteases
release soluble stimuli
through a process known as
ectodomain shedding.

Mullooly et al, 2016

 Release of Chemical Stimuli
• Membrane-anchored stimuli
can be released via
ectodomain shedding.

• Some stimuli formed within

the cytoplasm can be
released directly through the
plasma membrane.

• Stimuli packed into vesicles

can be released via
exocytosis.

Berridge, 2014
 Chemical Stimuli
• Membrane-anchored stimuli can
activate adjacent (Juxtacrine).

• Stimuli can also feedback to

stimulate the same cell
(Autocrine).

• They can diffuse to stimulate

neighbouring cells (Paracrine).

• Stimuli can enter the

bloodstream to stimulate distant
cells (Endocrine).

Berridge, 2014
 Cell Signalling: Growth Factors
• There are numerous growth factors that act by stimulating the cell
cycle.

• They can activate signalling mechanisms responsible for inducing cell

proliferation.

• Many of these growth factors are grouped together into families.

Berridge, 2014
 Cell Signalling: Growth Factor Families
# Growth Factor Family Examples Function References

Epidermal Growth Factor EGF, Transforming Growth

1 Promote cell proliferation and differentiation in various tissues Carpenter (2016)
(EGF) Factor-α (TGF-α), Epiregulin

FGF-1, FGF-2, FGF-7

Fibroblast Growth Factor Promote angiogenesis, wound healing, and cell proliferation
2 (Keratinocyte Growth Factor), Ornitz and Itoh (2015)
(FGF) and differentiation in various tissues
FGF-8, FGF-21

Insulin-Like Growth Factor Regulate cell growth, differentiation, and metabolism in Le Roith and Yakar
3 IGF-1, IGF-2
(IGF) various tissues (2017)

Nerve Growth Factor NGF, Brain-Derived

4 Promote neuron survival, differentiation, and growth Hefti (2017)
(NGF) Neurotrophic Factor (BDNF)

Platelet-Derived Growth Promote cell proliferation and migration in various tissues, Heldin and Westermark
5 PDGF-AA, PDGF-BB
Factor (PDGF) particularly in wound healing (2017)

Transforming Growth Regulate cell growth, differentiation, and migration in various

6 TGF-β1, TGF-β2, TGF-β3 Massagué (2016)
Factor-β (TGF-β) tissues, particularly in immune response and wound healing

Vascular Endothelial Ferrara and Adamis

7 VEGF-A, VEGF-B, VEGF-C Promote angiogenesis and vasculogenesis
Growth Factor (VEGF) (2016)
Cell Signalling: Growth Factors

Berridge, 2014
 Cell Signalling Pathways
• Signalling pathways may
co-operate with each
other to mediate the
action of growth factors.

• Components coloured in
red are responsible for
conveying signals from
the cell surface into the
nucleus.

Berridge, 2014
 Cell Signalling Pathways
• Signalling Components
include:
- Transcription factors
- Calcium
- Protein kinases such as
Extracellular-signal-
Regulated protein
Kinase 1/2 (ERK1/2)
and Protein Kinase B
(PKB) that target
transcription factors
resident within the
nucleus.
Berridge, 2014
 Cell Signalling Pathways
• These transcription
factors control the
expression of cell cycle
components that are
required to induce DNA
synthesis.

• The target cell can then

proceed to S phase.

Berridge, 2014
Cell Signalling: Growth Factors

Berridge, 2014
Receptor Kinases

Berridge, 2014
 Protein Tyrosine Kinase-linked Receptors
• ERBB receptor subunits are Protein
Tyrosine Kinase-linked Receptors
(PTKRs) or RTKs.

• They dimerise once activated.

• Their cytoplasmic domains can then trans-

autophosphorylate their own tyrosine
residues.

• Receptor activation leads to the activation of

transducers, which then set off a signaling
cascade.

Berridge, 2014
Tyrosine-Kinase Linked Receptor Family

Berridge, 2014
Tyrosine-Kinase Linked Receptor Family

Berridge, 2014
ERBB1/HER1/EGFR
Questions?