Research interests
Cancer, inflammation, diabetes and many other diseases can be considered to be the result of deregulated signalling pathways that normally enable the cell to properly respond to environmental changes. Phosphoinositides are a family of seven lipid messengers that are present in many subcellullar compartments (figure 1 ). Specific subcellullar phosphoinositide profiles are controlled by kinases, phosphatases and phospholipases which respond to both extracellular and intracellular cues. In this manner phosphoinositides transduce environmental stimuli into downstream cellular responses. Amongst other mechanisms phosphoinositides transduce signals by interacting with proteins to change the proteins intracellular location or function (figure 2).
We are particularly interested in phosphoinositides in the nucleus. While it is still not clear how phosphoinositides are presented in the nucleus nor how they are controlled we and others have shown that their levels are changed in response to many different types of stimuli and that they are able to interact with and regulate proteins that are involved in nuclear functions such as transcription, mRNA processing and export and DNA conformation. One specific protein domain that appears to act as a nuclear receptor for phosphoinositides is called the PHD finger, which is a zinc finger that is present in proteins that are predominantly nuclear and that are involved in epigenetic signalling. Epigenetic signalling is essentially a mechanism by which environmental stimuli can impact on both short and long term gene transcriptional output and thereby control cell fate decisions. DNA is wrapped up into nucleosomes by its interaction with histone proteins which then form higher order structures called chromatin. Chromatin forms at least seven different molecular structures which are differently associated with trasncriptional output. In essence epigenetic signalling involves the reversible enzymatic modification of DNA and of the histone proteins which appears to modify chromatin structure. Many of the proteins involved in placing (writers), removing (erasers) and interpreting (readers) these modifications can interact with and be regulated by nuclear phosphoinositides. For example TAF3 is a component of the multisubunit basal transcription complex that has a PHD finger that interacts with phosphoinositides. We showed recently that its interaction with phosphoinositides changes its ability to regulate muscle specific gene transcription and thereby muscle cell differentiation (figure 3). In this study we also showed that many other PHD finger containing proteins interact with phosphoinositides (DOI: http://dx.doi.org/10.1016/j.molcel.2015.03.009)
Our goal is to understand exactly how nuclear phosphoinositides are regulated, how they impact on nuclear functions and how they are deregulated in diseases. As the enzymes that modulate nuclear phosphoinositides are inherently druggable we believe that they will provide novel molecular targets with which to combat various diseases.
Figure 1: the profile of phosphoinositides defines identity and function of subcellular compartments. Different phosphoinositides appear to confer identity to subcellular compartments. By interacting and regulating specific proteins these phosphoinositides also confer subcellular specific functions (see figure 2)
Figure 2. phosphoinositides control cellular processes by interacting with specific proteins. Different phsophoinositides can interact with proteins through specific domains. For example PtdIns3P interact strongly with FYVE domain containing proteins, while PtdIns(4,5)P2 interacts with a sub-family of PH domain containing proteins. The interaction induces phosphoinositide specific control of downstream processes.
Figure 3. TAF3 is a PHD finger containing proteins that confers phosphoinositidide sensitivity to the basal transduction complex. The PHD finger of TAF3 interacts with nuclear PtdIns5P to regulate muscle specific gene transcription and thereby control muscle cell differentiation.
Research group
Molecular and Cellular Biosciences
Research project(s)
Epigenetic signalling and nuclear phosphoinositides.
Nuclear PI5P regulates the basal transcription complex by interacting with the PHD finger of TAF3. Deregulation of TAF3 by PI5P interaction impacts on muscle cell differentiation.
Regulation of cell division is coordinated by multiple signaling pathways and involves plethora of different activities. Kinases and phosphatases are among enzymes that are involved in this process. Here we want to contribute to a better understanding of how these enzymes control mitosis, specifically chromosome segregation.
