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Summary SSA6 Signal transduction
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Summary and WG answers SSA6 Signal transduction of the course MBO (molecular biology and oncology) at Leiden University.
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SSA6 Signal transductionChapter 6 Weinberg
Proteins is a signal trasnduction pathway have to be able to communicate very specifically.
This can be complicated as many proteins, like the kinases, have many paralogs (common
evolutionary origins an structure). The proteins thus have to enable themselves to be
specific, but must also come in contact with their targets quickly.
6.1 A signaling pathway reaches from the cell surface into
the nucleus
When there is serum starvation (absence of mitogens), cells go into a quiescent state called
G0. When you then add normal serum again, there will be synchronous growth and division.
There is a rapid change in the cell behavior. Within less than an hour, there is transcription of
around 100 genes called the immediate early genes (IEGs) after adding the fresh serum.
Cycloheximide is a chemical that stops protein synthesis. Using this showed that all the
proteins that are necessary to induce the IEG transcription are already in the cell and there is
no need for de novo synthesis. Some of the IEGs induce a second wave of gene expression.
Others may act as growth factors or help to construct the cytoskeleton.
Most of the proteins have a half life time. The level of the protein may act as an indicator for
the amount of mitogens nearby.
The second wave of genes that are being transcribed are called the delayed early genes.
Their expression is largely blocked by cycloheximide so their expression depends on de
novo synthesis of proteins.
Adding mitogens to cells also
increases the protein production
rate because there Is functional
activation of proteins that enable
ribosomes to initiate translation.
Growth factors can also induce
motility of cells or reorganization of
the cytoskeleton. Many growth
factors also provide a survival
signal to the cell.
Short term transcriptional
responses to mitogens provide no
indication of gene expression in
continuously growing cells. There is
thus a difference in the expression
of genes between a serum starved
cell that is now exposed to
mitogens and a cell that always is
exposed to them. This is because a
lot of the IEGs also act as a
repressor for there own gene (like
fos). There are a lot of negative
feedback loops like this.
, 6.2 The Ras protein stands in the middle of a complex
signaling cascade
Sos (son of sevenless) is a guanine nucleotide exchange factor
(GEF) of G proteins like Ras. It replaces GDP with GTP to
activate the G protein. Shc, Grb2 and Crk function as adaptor
proteins, so a sort of physical bridge between the growth factor
receptor and Sos.
6.3 Tyrosine phosphorylation control the
location and thereby action of many
cytoplasmic signaling proteins
A tyrosine kinase receptor can phosphorylate tyrosine residues
on cytoplasmic proteins so that they change their conformation
(stereochemistry). Another thing is that the receptor can
phosphorylate its own tail to alter the physical location of
downstream signaling partners. The latter one seems to be the
most important.
The Src proteins has three distinct amino acid sequence
domains that are called SH1-3. The SH1 is the catalytic domain
which is also seen in many RTKs. The SH2 domain is a sort of receptor and has a binding
site for a tyrosine phosphorylated ligand which enables It to associate with partner proteins.
Linked to this domain can be another catalytic domain which may also be involved in a
negative feedback mechanism (like a tyrosine phosphatase) An example of this is SHP1
which removes the phosphatases on the tail of the receptor (like the one for EPO).
Individuals with a mutation in SHP1 have less negative feedback and have hyperactive EPO
receptors and therefore more red blood cells which can be beneficial for sport.
Many receptors make use of this; they phosphorylate their tail on certain tyrosine residues so
that they become attractive homing sites for SH2 containing proteins that then attach.
SH2 binds to phosphotyrosine
SH3 binds to proline-rich regions
PH binds to PIP3
Many of these binding domains have become attached to catalytic domains (kinases, GAPS,
PLC). Others with these domains basically work as adaptors, which are a sort of linker/bridge
proteins.
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