Control of Inositol-Lipid Signalling

Lipid Signalling Team

Section: Section of Cell and Molecular Biology including the Cancer Research UK Tumour Cell Signalling Unit

M Katan, TD Bunney, R Baxendale, K Everett, I Garcia-Murillas, MS Alves Martins, Christopher Kimberley and Alessia Arduin

The focus of our team is the control of inositol-lipid signalling in processes underlying the generation and progression of tumours. Our aim is to define the mechanisms, extent and importance of the key signalling components, in particular the phosphoinositide-specific phospholipase C (PI-PLC) enzymes in subverting cell proliferation and motility in different types of cancer. Several additional projects address some of the more basic principles of enzyme activation and intermolecular interactions using multidisciplinary approaches.

PI-PLC-catalysed formation of the second messengers, inositol 1,4,5-trisphosphate and diacylglycerol, from its substrate phosphatidylinositol 4,5-bisphosphate (PIP₂), constitutes one of the major cell signalling responses. There are six families of PLC enzymes (PLCβ, γ, δ, ε, ζ and η) consisting of 13 isoforms in humans.

Among different isoforms of the PI-PLC, PLCγ has been recognised as a regulator of cell motility. Our work provided new insights into the involvement of PLCγ in cell migration. We have shown that PLCγ is involved in cell migration more widely than previously suggested and that in addition to growth factor-triggered chemotaxis, PLCγ is stimulated through integrin activation in different cancer cell types and endothelial cells. As a part of a collaborative work, we have demonstrated the first gain-of-function mutation in a PI-PLC molecule and, furthermore, that this mutation is linked to dramatic phenotypic disorder, autoimmunity and inflammation. Our structural and mechanistic studies have also shown that PLCγ2 could be regulated directly by a GTPase Rac that has an important function in cell motility. We are continuing studies of PI-PLC isoforms with the aim to better define the molecular details of their regulation and possible subversion of these regulatory mechanisms in disease; further structural and mechanistic studies remain an important approach.

Another PI-PLC enzyme, PLCε has been characterised as an effector of Ras, an important oncogene. In our studies we have demonstrated unique properties of the interaction between Ras and PLCε. Comparison of the individual Ras-interaction surfaces from PLCε and from other well-characterized effectors, Raf kinase, PI3-kinase and RalGDS, demonstrates that each surface has a specific binding signature to Ras. The unique properties of these interactions are reflected in different binding constants, energies of interaction, relative preference to members of the Ras family and mechanism of regulation. Activating mutations in the Ras oncogenes are involved in the formation of some 15% of all human tumours; furthermore, these mutations are particularly prevalent in human cancers that respond poorly to current treatments. As in many tumour cells oncogenic Ras is required to maintain the transformed phenotype, Ras itself and the proteins implicated as Ras effectors have been the subject of extensive research. However, as some 10 distinct functional classes of proteins have been implicated as Ras effectors, it is not clear which of these candidates are utilised by the oncogenic Ras in specific tumour types. We are currently addressing this question focusing on some of the candidate effectors, PLCε and Rassf proteins.

Further information about our team and research can be found on our website: http://www.lipidsignalling.org.uk/ aimed at those more specifically interested in lipid-signalling and those considering joining our team as PhD students or Postdoctoral Fellows.

External Funding: Cancer Research UK; Medical Research Council; Biotechnology and Biological Sciences Research Council; Engineering and Physical Sciences Research Council