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Summary SSA5 Growth factors and receptors
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Summary and WG answers of SSA5 Growth factors and receptors of the course MBO (molecular biology and oncology) at Leiden University.
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SSA5 Growth factors andreceptors
Chapter 5 Weinberg
Normal cells have to receive growth factors for their division. The extracellular signal is
transferred to the cytoplasm via receptors (signal transduction). The EGF receptors are
encoded by four different genes (HER 1-4).
5.1 Normal metazoan cells control each other's lives
Normal versions of oncogenes are often part of a machinery that enables cells to receive and
process biochemical signals that regulate the cell proliferation. Cells continuously talk to
each other and a lot of the messengers are growth factors. To grow or not is always a
weighted decision and is dependent on more than just the cell. To make serum, blood needs
to clot and this causes platelets to release a lot of PDGF which is a potent stimulator of
fibroblasts. Growth stimulating factors are often called mitogens. Some growth factors, like
EGF, do not only cause proliferation but also change the shape of a cell.
5.2 The Src protein functions as a tyrosine kinase
It was discovered that Src was a kinase because antibodies that they used to detect the
oncoprotein became phosphorylated when bound. This was pure by chance as Src does not
normally do this. Src is a phosphoprotein meaning that it carries covalently attached
phosphate groups. The Src kinase can phosphorylate many other proteins (like other protein
kinases) which was revealed by an experiment in which they transformed NIH 3T3 cells with
, oncogenic src and then performed a gel electrophoresis to detect phosphorylated proteins (a
lot of them!).
Src is a tyrosine kinase (there are also serine and threonine kinases). Phosphotyrosine is
much more rare. When transforming cells, the phosphotyrosine became a much bigger part
of all the phosphoaminoacids.
5.3 The EGF receptor functions as a tyrosine kinase
Because of amino acid sequencing, it was found that there was a connection between
signaling proteins and the oncoproteins.
The N terminal of the EGF-R is large and
protrudes into the extracellular space
(ectodomain) and it can recognize the
ligand EGF. The transmembrane domain
is short and has a hydrophobic amino
acid sequence. The C terminus extends
into the cytoplasm. This cytoplasmic
domain revealed similarity with the Src protein. Sequencing of the amino acids revealed
many other tyrosine kinases which often also function as oncoproteins. Also a lot of other
receptors have been identified; the receptor tyrosine kinases.
Depending of the receptor, it can trigger multiple biological responses including growth,
division, change in cell shape, survival and motility.
5.4 An altered growth factor receptor can function as an
oncoprotein
The erbB oncogene is very similar to the EGF receptor, but misses a part of the ectodomain.
Therefore it cannot recognize EGF anymore, but still it could signal. These truncated
versions are also found in breast cancer and are called ErbB2/HER2/Neu. Mutations and
deletions can trigger ligand-independent firing of the receptor. This can also be causes by
enormous overexpression of the normal receptor (mass-action can cause spontaneous
dimerization). Besides this, it can be the case that there is autocrine signaling as the cancer
cell produces a lot of the ligand.
Receptor overexpression can have multiple causes. It can be that there is just
overexpression because more of the gene is transcribed. It can also be that the lifetime of
the receptor is expanded because there is less endocytosis of ti. Can also be more recycling
of the receptor. As an example, overexpression of HIP1 prevents normal endocytosis of the
EGF receptor. GAK is a strong promotor of endocytosis of the EGF-R so less expression of
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