Research

PTEN regulation:

Acidic Lipids: PTEN has an N-terminal PI(4,5)P2 binding motif that appears to be responsible for much of the preference of the phosphatase for PIP3 substrate molecules that are present in acidic membranes rich in PI(4,5)P2, such as the plasma membrane of most cells Walker et al, 2004

Phosphorylation: PTEN has at least 2 clusters of serine and threonine phosphorylation sites that can regulate PTEN activity and stability. We are currently interested in the functions of a pair of sites, Thr366 and Ser370, that are phosphorylated by GSK3 and CK2 respectively. Maccario et al, 2007, Tibarewal et al, 2012

Oxidation: As a member of the Protein Tyrosine Phosphatase superfamily, the catalytic mechanism of PTEN relies upon a reactive active site cysteine nucleophile that is sensitive to oxidation. Many cellular stimuli that activate PI3K, such as many growth factors, also stimulate the production of reactive oxygen species that oxidise and therefore inactivate a fraction of the cellular PTEN and contribute to the accumulation of PIP3 and the activation of downstream signalling. We are currently trying to study the significance of this regulatory mechanism in different PTEN regulated processes. Leslie et al, 2003, Leslie, 2006, Ross et al, 2007

Ubiquitination: PTEN is both poly-ubiquitinated and mono-ubiquitinated, seeming to control PTEN stability and nucleo-cytoplasmic shuttling respectively. We have recently found that either poly- or mono-ubiquitination of PTEN inhibits its activity in vitro. Additionally, PTEN ubiquitination can be stimulated by hyperosmotic stress, correlating with large increases in the levels of its substrate PIP3. We are now keen to investigate whether this apparent mechanism by which PTEN activity can be turned off in response to the extracellular environment is a widespread and more generally significant process, with potential importance during tumorigenesis. Maccario et al, 2010.