Detailed Summary Drug Targets Biochemistry and Signaling
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XM_0111 (XM_0111)
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Vrije Universiteit Amsterdam (VU)
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Cell Signaling
Made this summary for DRUG TARGETS BIOCHEMISTRY AND SIGNALING.
Summary is detailed and complete. However, chapter 11 and 12 were not saved correctly. These are lost. I had a printed backup which is scanned and included in this summary. The quality is the same as the rest of the summary. The only ...
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Lecture 1: Introduction............................................................................................................................ 2
Lecture 2: Information transfer across the membranevia signaling mediators...................................... 8
Lecture 3: Compound approval and repurposing ................................................................................. 18
Lecture 4: Protein kinases; an important drug target family ................................................................ 26
Lecture 5: Technologies......................................................................................................................... 32
Lecture 6: ABC of GPCR signaling .......................................................................................................... 43
Lecture 9: Wnt signaling in (mammary) development and (breast) cancer ......................................... 56
Lecture 10: Development of single domain antibody fragments from camelids.................................. 65
,Lecture 1: Introduction
Most of the drugs that are in the market are interfering with molecules that are very important in cell
signaling. The G coupled receptors are involved in different signaling pathways. Also they are involved
in certain pathological situations in which signaling is not regulated. The main focus is not only on
producing peptides that target certain molecules. But also on the molecules which should be targeted.
You want to hit the right protein, but you don’t want to interfere too much with the healthy situation.
What we are actually looking at, is the decision making network in the cell. This network is very
complex as it is involved in many different networks.
If we talk about communication on the level of individuals, then multiple individuals can come up with
a strategy (to win a game for instance). This communication is between organisms, but it also needs
to correct functioning of the individual to stick to this strategy. Steering the organism, that is something
that happens in the brain. The individual neurons are the machines that steer the individual bodies.
Cells need to be able to communicate. If you take a yeast cell, division of the mother cell needs to be
performed in a very controlled timely fashion. Only if the daughter cell can survive on its own, cell
division can happen. So there needs to be communication in the sense whether the daughter cell is
viable. Do we have the possibility to make a whole in the cell wall, that it could still survive, are the
nutrition levels high enough? There are lots of decision that need to be made in such a simple system.
And it involves the intergraded communication of many different communications between cells.
The network in signaling pathways, needs to be coordinately active and needs to be organized in a
coordinated way, in order to allow cells to devide in a proper way. This network of signaling consists
of individual signaling pathways. The individual signaling pathways consist of individual signaling
molecules.
Every cellular adaptation/change will be properly times and properly localized, in order to allow the
process to be performed in the right way. The brain of the cell, is the system that controls the cell in
order to properly function together as a multicellular organism. Even signal cellular organisms need to
be able to adapt to their environment.
This has to take place in an environment that is very crowded. If you look at the amount of proteins in
the cell, you need to realize that it is enormously crowded. These signals needs to be isolated well
enough, so that it cannot give any false signals. Protein kinases for instance, several amino acids can
be phosphorylated. An individual protein kinase can be phosphorylated, in order to become active.
You allow the activated kinase to be associated with different target proteins. Within the testtube,
then you will see that the protein kinase can phosphorylate lots of targets. There are target sequences
that are preferentially phosphorylated. These kinds of target sequences needs to be discovered. In
principal, there are more targets that can be phosphorylated, than targets that needs to be
phosphorylated in certain conditions.
It is important to realize, that when you talk about signal transduction, you are not only talking about
activating downstream signals, but also about localization and organization of this activity. There are
large complexes of proteins that function, and are isolated. If this is not organized, things can go wrong
and all kinds of unwanted proteins get activated.
Studying these kinds of events, needs to be done as much as possible in a cellular context. In vitro
assays are still important, to get an idea what the proteins are doing. But is doesn’t tell you how it is
regulated and how it is finding its downstream targets.
, In mammalian cells, there is no harm in studying
signal transductions in single cell organisms. This is
because a lot of pathways are very well conserved.
In principal the main interest will be on the
mammalian signaling. If we talk about signals that
needs to be sensed by any type of cell, this needs to
be transferred in some kind of response. We talk
about internal ques. In the right part of the green
halve, you see the internal states of the cell. The cell
needs to be aware of its nutrition condition, the
ionic balance, internal pH and the state of the cell
cycle. All types of external ques have to be
integrated into the cycle to allow the cell to only
devide when it is possible.
In cancer the ques are not regulated. Not only internal, but also external ques needs to be sensed. If
you look at nutrition signals, there is an internal and an external part. Some cells need to take in some
nutrients. The cells in the tissue needs to be aware of the surrounding and the extracellular matrix.
Signals from other cells needs to be integrated. This is just an simple overview of the input that needs
to be transduced into an output. This output can consist of a new set of genes that can be switched on
and off. Cells that are triggered to move to a certain position in the body, need to undergo
morphological changes. If cells are damaged or harmed, they need to be able to communicate with
the immune system. In order to do so, the production of cytokines and chemokines needs to be
activated. So cells needs to sense damage, but also unwanted organisms. Upon sensing these events
the chemokines needs to be upregulated and secreted. Growth and cell division are important
responses. Unwanted growth and cell division is a big issue. In some cases senescence or apoptosis
needs to be triggered, when the damage is that large that the cell cannot repair the damage anymore.
These decisions are really important for healthy situations. If we think about developmental biology,
growth and differentiation pathways needs to be organized, in order to allow a new organism to grow.
In our body lots of long term responses are regulated by the excretion of hormones. So cells needs to
be capable to sense the hormones and response in a proper way. In case of infections or cellular
damage, the immune system needs to be alerted. For the activation of the immune cells, signal
transduction is important. Dysregulation can cause all kinds of inflammatory situations.
If you think about signal transduction, the responses and the triggers are signals that are in a
code. They need to be sensed by receptor proteins. These are not only exposed on the outside
of the cell, but there are also receptors inside the cell that can pick up the signals. The signal
itself can be a ligand or a mechanical situation or a osmotic signal that needs to trigger change
in the receiving molecule. This will result in a transmission of the signal. Cells are also capable
of sensing a gradient in chemokines for instance, this mediates direction for the immune
system to get to the point where they are needed. So it is not just, “there is a problem” but
also “the problem is in that direction”. In a lot of cases, a particular signal is not aiming in
triggering just one kind of signal that needs to be triggered. All signals work together to form
the proper response. And if something works, there is a tendency to conserve that pathway.
In the picture you could see the pathway for cell division, which is also conserved in D.
melanogaster and C. elegans. The red components can be mutated, which can trigger tumor
proliferation. Sometimes you can even change one of the compounds with homologous of
different species.
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