Trends in Cell Biology
ForumPTEN: a tumour suppressor that functions as a phospholipid phosphatase
Section snippets
A search for PTEN substrate(s)
Reports describing the first example of a tumour-suppressor gene with sequence identity to the PTPases stimulated numerous groups to search for potential protein substrates for the phosphatase. Yamada and his colleagues10, 11 reported that PTEN overexpression leads to changes in cell migration and dephosphorylation of focal adhesion kinase (FAK). Biochemical studies from our laboratory12 and others13 noted that recombinant PTEN poorly dephosphorylated a number of artificial substrates. In fact,
The PTEN signature sequence?
If PTEN acts to dephosphorylate PtdIns(3,4,5)P3 in vivo, it is reasonable to question whether PTEN bears any similarity to enzymes known to catalyse the dephosphorylation of inositol phosphates or phosphoinositides. Majerus and colleagues23 have described a family of metal-dependent/Li+-inhibited inositol phosphatases that have structural similarity to the fold of fructose 1,6-bisphosphatase. This family of proteins shares a metal-binding sequence and bears no resemblance to the Cys(X)5Arg
Genetic analysis of PTEN in the worm
Several of the steps involved in insulin signalling in mammals are conserved in the nematode Caenorhabditis elegans (Fig. 2). The DAF-2 protein of the worm functions in a manner similar to the complex between insulin receptor and IRS. DAF-2 appears to activate AGE-1, a protein with sequence identity to the p110 catalytic subunit of PI3K, which produces PtdIns(3,4,5)P3. There are two C. elegans AKT/PKB homologues (AKT-1 and AKT-2) that are genetically downstream from AGE-1 and would be expected
How is PTEN regulated?
Although this is a very important question, there is almost no information on PTEN regulation aside from the fact that PTEN mRNA levels are modulated by transforming growth factor β28. In addition to control of the transcriptional activity of the gene encoding PTEN, it is likely that the subcellular location of the phosphatase is carefully modulated. It might be anticipated that the cell employs an organization centre or scaffold to generate local concentrations of PtdIns(3,4,5)P3 as a result
Acknowledgements
This work was supported by grants from the NIH, NIDDK 18849 and 18024 to J. E. D. and by the Walther Cancer Institute.
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