Evolution of Cellular Networks
Our group studies how cellular functions have diverged during evolution as well as how they are altered in disease. We study the molecular sources of phenotypic novelties, exploring how DNA changes are propagated through molecular structures and interaction networks to give rise to phenotypic variability.
We use post-translational modifications (PTMs) data from mass-spectrometry experiments to study the evolutionary dynamics and functional importance of post-translational regulatory networks. We aim to reconstruct the ancestral states of PTM regulatory networks in order to understand how some of the wondrous cellular functions that exist today were like in their primitive forms. For this we develop approaches to infer the history of protein modifications; the determinants of specificity for PTM regulators; and the ways protein function is controlled by PTMs.
We are also increasingly interested in understanding how these regulatory systems make decisions in present day species and how they are re-wired in the context of disease (e.g. cancer or infection). We have assembled a collection of conditional phosphoproteomic experiments (phosphate.com) that we have used to study human kinase regulation and the space of signalling states of cells. We are now studying how genetic variation seen in cancer cells changes their signalling state with an aim to understand context dependent cellular vulnerabilities to drugs.
Beyond PTM regulatory networks we are broadly interested in studying why different individuals or species diverge in their response to drugs, other environmental perturbations or additional genetic changes. For this purpose we are developing a general propose framework to predict the molecular consequences of DNA changes (www.mutfunc.com) and using these to guide genotype-phenotype associations.
Invergo BM, et al. Sub-minute Phosphoregulation of Cell Cycle Systems during Plasmodium Gamete Formation. Cell Rep. 2017 Nov 14;21(7):2017-2029.
Gonçalves E, et al. Widespread Post-transcriptional Attenuation of Genomic Copy-Number Variation in Cancer. Cell Syst. 2017 Oct 25;5(4):386-398.e4.
Studer RA, et al. (2016) Evolution of protein phosphorylation across 18 fungal species Science Vol. 354, Issue 6309, pp. 229-232
Ochoa D, et al. (2016) An atlas of human kinase regulation Mol Sys Bio 12, 888
Wagih O, et al. (2015) Uncovering phosphorylation-based specificities through functional interaction networks Mol Cell Proteomics
Strumillo & Beltrao (2015) Towards the computational design of protein post-translational regulation Bioorg Med Chem, 23, pp. 2877–2882
EvoCellNet group news
- New lab preprint on kinase specificity from David Bradley: "Global analysis of specificity determinants in eukaryotic protein kinases"
- Brandon's work has been published in Cell Reports - "Sub-minute phosphoregulation of cell-cycle systems during Plasmodium gamete formation"
- Emanuel Goncalves' project on CNV attenuation is now online in Cell Sytems - "Widespread Post-transcriptional Attenuation of Genomic Copy-Number Variation in Cancer"
- David Ochoa's manuscript - "An Atlas of Human Kinase Regulation" was published in Mol Sys Bio. See also accompanying resource Phosfate