2. Cell signaling has been most extensively studied in the context of human diseases and
signaling between cells of a single organism. However, cell signaling may also occur
between the cells of two different organisms.
Cell signaling can be classified to be mechanical and biochemical based on the type of
the signal. Mechanical signals are the forces exerted on the cell and the forces
produced by the cell. These forces can both be sensed and responded by the cells .
Biochemical signals are the biochemical molecules such as proteins, lipids, ions and
gases. These signals can be categorized based on the distance between signaling and
responder cells
2
3. Higher organisms, are comprised of cells.
The cells often unite to form tissue which come together to form
organs which together make up the organism.
Cells of an organism do not live in isolation.
The communication between cells ultimately controls growth,
differentiation, and metabolic processes within the organism.
Communication between cells is often by direct cell to cell
contact.
Communication frequently occurs between cells over short and
long distances.
3
4. In cases of short and long distance communication, a substance may be
released by one cell and recognized by a different target cell.
In the target cell, a specific response is induced.
Cells use an amazing number of signaling chemicals.
These signaling molecules are termed “hormones.”
The ability of a hormone to induce a response in a target cell is usually
mediated by a hormone receptor on, or in, the target cell.
4
5. An animal cell depends on multiple extracellular signals
5
7. Tyrosine kinase receptors are a family of receptors with a similar structure. They each
have a tyrosine kinase domain (which phosphorylates proteins on tyrosine residues),
a hormone binding domain, and a carboxyl terminal segment with multiple tyrosines
for autophosphorylation. When hormone binds to the extra cellular domain the
receptors aggregate.
7
8. When the receptors aggregate, the tyrosine kinase domains
phosphorylate the C terminal tyrosine residues. 8
9. This phosphorylation produces binding sites for proteins with SH2
domains. GRB2 is one of these proteins. GRB2, with SOS bound to it,
then binds to the receptor complex. This causes the activation of SOS.
9
10. SOS is a guanyl nucleotide-release protein (GNRP). When this is
activated, it causes certain G proteins to release GDP and exchange it for
GTP. Ras is one of these proteins. When ras has GTP bound to it, it
becomes active. 10
11. Activated ras then causes the activation of a cellular kinase called raf-1.
11
12. Raf-1 kinase then phosphorylates another cellular kinase called MEK.
This cause the activation of MEK. 12
13. Activated MEK then phosphorylates another protein kinase called MAPK causing its
activation. This series of phosphylating activations is called a kinase cascade. It results
in amplification of the signal. 13
14. Among the final targets of the kinase cascade are transcriptions factors (fos and jun showed
here). Phosphorylation of these proteins causes them to become active and bind to the DNA,
causing changes in gene transcription. 14
17. The HER2 signaling network
• Human epidermal growth
factor receptor 2 (HER2) is
a member of the ErbB
family of receptor tyrosine
kinases (RTK).
• Ligand binding induces
receptor dimerization and
phosphorylation of tyrosine
residues in the C-terminal
tail segments.
• Tyrosines serve as docking
sites for signaling
molecules, activating
molecular pathways such as
cellular proliferation.
• Overexpression of HER2
results in ligand-independent
activation and occurs in 20-
30% of human breast
cancers.
17
20. PI3K (Phosphatidylinositol-3-kinase) is a group of enzymes involved in cellular growth,
proliferation, differentiation, cell motility, intracellular trafficking, and survival that play
very important roles in developing breast cancer.
PI3K (Phosphoinositide 3-kinase) is activated by survival factors or transforming
events such as HER2 overexpression/activation. Activated PI3K generates
phosphoinositides causing translocation of AKT to the plasma membrane, where it is
phosphorylated and activated. Activated AKT can then phosphorylate numerous
targets. Activated AKT negatively regulated by the antagonising action of
phosphatase and tensin homologue (PTEN) on PI3K .
HER2 overexpresstion, undergoes proteolytic cleavage which results in
the release of the extracellular domain and in the production of a truncated
membrane-bound fragment (p95).
20
25. Trastuzumab is the first of such agents which was registered for use in
patients with HER2-overexpressing breast cancer.
A proposed mechanism of action of trastuzumab is the reduction of the signalling
from these pathways, thus promoting apoptosis and the arrest of proliferation.
Diminished receptor signalling may result from trastuzumab-mediated internalisation
and degradation of the HER2 receptor, but, as discussed above, it is unclear whether
trastuzumab actually down-regulates HER2. An alternative mechanism by which
trastuzumab may block PI3K signalling , who demonstrated that trastuzumab
specifically inhibits PI3K signalling by increasing PTEN membrane localisation and
phosphatase activity. This in turn leads to rapid AKT dephosphorylation and inhibition
of cell proliferation.
25
26. ADCC is mainly due to the activation of natural killer cells (NK), expressing the Fc gamma receptor,
which can be bound by the Fc domain of trastuzumab. This event activates the lysis of cancer cells bound to trastuzumab
26
33. Mechanism of RNA Interference (RNAi)
• Long double-stranded RNAs (dsRNAs; typically
>200 nt) can be used to silence the expression
of target genes in a variety of organisms and
cell types (e.g., worms, fruit flies, and plants).
• In mammalian cells, introduction of long dsRNA
(>30 nt) initiates a potent antiviral response,
exemplified by nonspecific inhibition of protein
synthesis and RNA degradation. The
mammalian antiviral response can be bypassed,
however, by the introduction or expression of
siRNAs.
33
