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October
28, 2010
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A team
of scientists at the Institut de recherches cliniques de
Montréal (IRCM) led by Dr. Jean-François Côté, Director
of the Cytoskeletal Organization and Cell Migration research
unit, identified a novel molecular mechanism in the control
of cell motility. Their findings were published online today
in Current Biology, a journal from the Cell Press
group. This scientific breakthrough could eventually lead
to the development of new cancer-treating drugs that could
block the spread of tumours (metastasis).
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"As many as
90% of cancer patient deaths are attributable to metastasis, which
explains the importance of understanding the molecular mechanisms
at the basis of this harmful process," says Dr. Côté. "This is
why, over the past few years, we have focused our research on
DOCK180, a protein involved in intracellular signalling networks,
and more particularly on the DOCK180/Rac1 signalling pathway,
which is suspected to be a key mediator of tumour metastasis."
Unlike normal
cells that migrate throughout embryonic and adult life to perform
their specialized functions, cancer cells metastasize in order
to lethally spread throughout the body. At a molecular level,
DOCK180 specifically activates the small Rac1 protein, which,
in turn, modifies a cell's shape and promotes cell motility and
invasion. Dr. Côté's team had previously demonstrated in detail
how DOCK180, with the help of its binding partner ELMO, acts on
Rac1 to promote robust cell migration.
"We knew that
this signalling pathway had to be regulated to prevent uncontrolled
cell migration in normal conditions, but until now, the mechanisms
involved had been eluding us and other scientists," explains Manishha
Patel, a PhD student in Dr. Côté's laboratory and co-author of
the study. "With our recent findings, we demonstrated that the
ELMO protein closes in on itself to enter a repressed state, thus
preventing the activation of the DOCK180/Rac pathway."
"Our team
identified three regions in ELMO that allow it to toggle between
a closed/inactive and open/active shape," adds Dr. Yoran Margaron,
a postdoctoral fellow in the same research unit and one of the
article's co-authors. "We showed that if we disrupt ELMO's regulatory
feature and maintain the protein in an open state, we can fully
activate the DOCK180/Rac pathway and significantly increase the
migration potential of cells."
The researchers'
next step is to investigate the regulation of ELMO in cancer cells.
Based on their latest findings, they will attempt to maintain
ELMO in a repressed state within cancer cells to prevent metastasis,
which could have a major impact on the development of potential
cancer treatments.
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This research
project was supported by the Canadian Institutes of Health Research
(CIHR) and the Canadian Foundation for Innovation (CFI). Other
collaborators for this study include Nadine Fradet, Qi Yang and
Brian Wilkes from the IRCM, as well as Dr. Michel Bouvier from
the Institut de recherche en immunologie et en cancérologie (IRIC),
and Dr. Kay Hoffman from Miltenyi Biotec in Germany.
Article via
Eurekalert
Contact: Julie
Langelier
julie.langelier@ircm.qc.ca
514-987-5555
Institut de recherches cliniques
de Montreal
For more information,
please refer to the online article published by Current Biology.
---An
Evolutionarily Conserved Autoinhibitory Molecular Switch in ELMO
Proteins Regulates Rac Signaling
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