It has been 4 years
since I started as a group leader at the EMBL-EBI (see past yearly reports – 1, 2 and 3). This year the group composition has been
mostly stable, with the exception of interns that have rotated
through the group. We had Bruno Ariano
(twitter)
visiting us for 6 months working on a project to build an improved
functional interaction network for Plasmodium. Matteo Martinis has joined the group for a few months and is working with David Ochoa on comparing in-vivo
effects of kinase inhibitors with their known in-vitro kinase
inhibition effects. Finally, Areeb Jawed has joined Cristina and Bede, for
some months, in their efforts to develop genetic methods to study
protein modification sites. I think we had a great year in terms of
publishing and I had the luxury of not trying to apply
for additional funding. That luxury is short lived as we have funding
that is ending this year that I will try to replace.
The one before the
four year review
All EMBL units are
evaluated every 4 years by a panel of external reviewers. The next review for the research at EMBL-EBI is coming up now in March and we have been preparing the
required documentation for this. Naturally this forced me to think
about what we have achieved as a group for the past 4 years and what
we aim to do for the next 4. It is impossible not to go through this
process without being drawn into some introspection and without comparing our performance with that of those around me. I
think we did well in this period of time, we got two significant
grants funded (HFSP and ERC) and published some articles that I feel
have been significant contributions towards the study of kinase signaling. I remember my interview for this position when they asked
me what I would expect to achieve in the next 5 years. My first
though was: “Really ? That question ?”, but I think we did
achieve we I had hoped at the time. Still, at EMBL-EBI we are
surrounded by some fantastic colleagues that keep the bar really
high. It is hard to be satisfied and I am certainly motivated by our
research environment to try to help our group to keep up the good
work. This review will also determine if our group receives a 4 year
extension after the first 5 years. I am confident but still
apprehensive and curious about what the reviewers will say.
Studying cell
signaling states using phosphoproteomics
During the past four
years we have worked on several aspects of kinase based cell
signaling. I mentioned before our work on trying to describe the
evolutionary history of protein phosphorylation (blog post) and to predict the
kinase specificity from interactions networks and phosphoproteomic
data (blog post). I haven't described yet our work on studying cell signaling
states that has been published a few months ago When David Ochoa started in the group around 3.5 years we
reasoned that, by collecting information on how phosphosites
abundances change across a large number of conditions, we would be
able to use the profile of co-regulation across conditions to learn
about how cell signaling systems work. This is copying by analogy
what has been done in gene expression studies since Mike Eisen's work. David made use of published conditional phosphoproteomic
studies to compile a very large compendium of different conditions.
There are issues related to the incomplete coverage of mass
spectrometry measurements and potential batch effects of the
different studies. David tried to work around these, primarily by
focusing the analysis on groups of phosphosites (e.g. targets of the
same kinase) instead of individual positions. Using this data he
derived an atlas of changes in activities for around 200 human
kinases across nearly 400 different conditions. We show in this work
how this can be used to advance our knowledge of kinase signaling
(Ochoa et al. Mol Sys Bio 2016, and the phosfate webserver).
For me this work was
the fist time we could measure a large number of cell signaling
states. To see what is the structure of this state-space and what we
can learn from this. What kinases are most often regulated ? What
kinases define particular signaling states ? What states act as
“opposing” states and how may we use this information to promote
or inhibit specific states or transitions through the state-space ?
These are all questions that we can address with this atlas. The fact
that the data was collected from different publications, using different protocols and machines will certainly have an impact on the
accuracy and resolution of this atlas. However, the quality and coverage
and these types of experiments will only improve and I think this
direction of research will continue to be exciting for long period
of time.
Since this work we
have also tried to benchmark different approaches to predict the
changes of kinase activity from phosphoproteomic information
(preprint). In collaboration with Julio Saez-Rodriguez's lab we
also used some of the same concepts to relate the changes of
metabolism with predicted changes in kinase, phosphatase and
transcription factor activities (Gonçalves et al. PLOS Comp Bio 2016).
Onto the next four
years
If I do get my
contract extension, we will continue our
current main research focus on studying cell signaling through the next four years. Although we
will certainly continue to study long term evolutionary trends, such
as the evolution of kinase specificity, we will complement this with
trying to understand the impact of genetic variation for individuals
of the same species with a strong focus on E. coli, S. cerevisae and
H. sapiens (mutfunc). We have started to make use of cancer data as
genetic resource to study human cell biology (preprint). We won't
necessarily try to study cancer as a disease but I think that datasets for primary tumors and cancer cell lines are amazing
resources to learn about how human cell biology and cell signaling
work. The group will have its first big turnover of group members
over the next 1 or 2 years which will be challenging professionally
and personally. However this turnover will also allow for and shape
future directions of the group which will also be exciting.