Scientists have been searching for it for decades: the
enzyme that cuts the amino acid tyrosine off an important part of
the cell's skeleton. Researchers of the Netherlands Cancer
Institute have now identified this mystery player, which may be of
vital importance to the understanding of cell function and
division, and therefore the understanding of cancer. They publish their finding in Science on
Just like the human body as a whole, each human cell has a
skeleton it needs for functioning properly. That so-called
cytoskeleton allows a cell to maintain its shape, move to different
places and transport molecules through its interior. Long chains
called microtubules (see image*) form an important part of that
skeleton and function as a highway for the transport of molecules.
For example, microtubules play a key role in cell division by
allowing the cell to meticulously align their chromosomes before
dividing them amongst daughter cells. Their crucial importance to
the cell is easily illustrated by the working mechanism of a widely
used group of cancer medicines called taxanes: they disrupt
microtubule function and thereby kill dividing cells.
It has been suggested that proper transport at this crucial moment
in the cell cycle involves detyrosination, in which the amino-acid
tyrosine is removed from the tail of one of the microtubules' main
building block: α-tubulin. Over the past four decades
scientist have been searching for the main actor in this process.
Despite its importance for several cellular processes it remained
unknown which enzyme takes off the tyrosine.
Researchers of the Netherlands Cancer Institute have now solved
this puzzle by unmasking the mystery player. By using their
recently developed innovate genetic screening method Joppe Nieuwenhuis and his
colleagues identified the small SVBP protein as being a crucial
part of the process. This small protein binds - and thereby
stabilizes - proteins called vasohibins, which appear to have
tubulin detyrosination activity. Nieuwenhuis: "These findings are
surprising, because vasohibins were thought to function outside the
cell and only recently it was predicted that these proteins might
function as enzymes, without knowing their function."
Now just how did Nieuwenhuis and his colleagues at Thijn Brummelkamp's lab find these key
molecular players? By using genome wide random mutations in human
cells containing just one copy of each gene. Subsequently they
selected the cells in which the studied process of detyrosination
was broken due to one of the randomly introduced mutations.
Selecting the cells with very little detyrosinated tubulin they
discovered these cells had a mutated (and therefore dysfunctional)
SVBP gene. Further experiments confirmed the interaction with
vasohibins and its effect on tubulin detyrosination.
"For cell biologists this could be an important step", says
Nieuwenhuis. "We have found a piece of the puzzle that scientist
have been staring at for many years because the process of
detyrosination was discovered 40 years ago. This knowledge could be
relevant to further understand the processes of mitosis, cell
migration and cancer development. It is already found that the
invasive front in some tumor tissues, where cells are migrating
most actively, contains a high amount of detyrosinated tubulin. It
is interesting to speculate that inhibition of detyrosination could
be beneficial under certain conditions."
Interestingly, in the same edition of Science a group of
French scientists reached similar conclusions using a biochemical
approach to identify detyrosinating enzymes.
*The image shows 6 melanoma cells. Their DNA (blue) is found in
the nucleus of the cells, their microtubules (red) in the
cytoplasm, surrounding the nucleus.