University College London

Professor Shamshad Cockcroft,
Lipid Signalling Group,
Dept. of Physiology,
Rockefeller Building, Fourth Floor Rm 421
21 University St.,
University College London
London WC1E 6JJ

The work funded by The Lowe Syndrome Trust has produced the following findings :

The X-linked oculocerebrorenal syndrome (Lowe Syndrome) is caused by a mutation of the OCRL1 protein, an enzyme that breaks down a unique phospholipid by removing a phosphate. The phospholipid, phosphatidylinositol(4,5)bisphosphate (PIP2) is special because it has a multiplicity of functions in cell signalling, modulation of the actin cytoskeleton and membrane traffic. The work that we have done has been published in two Refereed Journals, Cell signalling [1] and EMBO J. [2] ; the first piece of work has examined the impact of diminishing PIP2 levels on uptake of proteins in order to understand the Fanconi syndrome. The second piece of work was to establish an in vitro assay to monitor OCRL1 activity and to examine whether this activity could be regulated. One paper is being prepared for submission and compares the cell-line model to an in vivo model with respect to endocytosis of insulin in the kidney [3] .

Two major outcomes of our work are:

[1]  We have shown that endocytosis and Cell Signalling are intricately linked and that stimulation of Signalling negatively regulates endocytsosis. The possibility that a build-up of PIP2 in OCRL patients can lead to aberrant calcium signalling needs to be considered and this should be examined in a polarized epithelial cell model.

[2]  The activation of OCRL by a protein, Rab6 which functions as a molecular switch. Rab6 can cycle between the OFF position to ON position. In the ON position, it can bind to OCRL and increase the activity of OCRL. Future work should focus on identifying the upstream regulator of the Rab6 protein.

References

  1. N. Carvou, A. G. W. Norden, R. J. Unwin, S. Cockcroft, Signalling through phospholipase C interferes with clathrin-mediated endocytosis., Cell Signalling.  19 (2007) 42-51.
  2. N. Hyvola, A. Diao, E. McKenzie, A. Skippen, S. Cockcroft, M. Lowe, Membrane targeting and activation of the Lowe syndrome protein OCRL1 by rab GTPases., EMBO J.  25 (2006) 3750-3761.
  3. P. Kolman, A. Pica, N. Carvou et al., Insulin uptake across the luminal membrane of the rat proximal tubule in vivo and in vitro., Am J Physiol Renal Physiol.  Submitted (2008)