Arresting times for PTEN.

The tumour suppressor PTEN (phosphatase and tensin deleted on chromosome 10) is an important regulator of cell proliferation and migration. In this issue of The EMBO Journal, Lima-Fernandes and colleagues show that the universal signalling scaffold protein, b-arrestin dynamically interacts with PTEN, through a phosphorylationcontrolled switch. This protein–protein interaction profoundly influences the ability of PTEN to regulate both cell proliferation, through activation of its lipid phosphatase activity, and enhance cell migration by unblocking the inhibitory effect of the PTEN C2 domain and by recruiting activated ROCK into a b-arrestin/PTEN ‘signalosome’. Understanding the myriad of mechanisms that contribute to cell proliferation and migration, and how these are modified in various cancers, will point the way to new, personalized diagnostics and therapeutics. The tumour suppressor PTEN (phosphatase and tensin deleted on chromosome 10) regulates numerous key cellular functions including proliferation and migration with its relevance to normal cell physiology exemplified by the fact that its gene is frequently deleted or mutated in a wide variety of human cancers (Leslie and Downes, 2002; Salmena et al, 2008). In this edition of The EMBO Journal, Lima-Fernandes et al (2011) show, for the first time, that at the cross-roads controlling the proliferative and migratory determining aspects of PTEN is the universal signalling scaffold protein, b-arrestin (Defea, 2008). The discovery that b-arrestins serve as upstream signalling regulators of PTEN is likely to have important consequences for our understanding of progression and metastasis associated with certain types of cancer and to point towards the development of novel diagnostic and therapeutic approaches. PTEN exhibits dual-specificity phosphatase activity able to dephosphorylate not only lipids, of which its major physiological substrate is phosphatidylinositol 3,4,5 trisphosphate (PIP3) but various tyrosine phosphate containing peptides. It is, however, by degrading PIP3 into phosphatidylinositol 4,5 bisphosphate (PIP2) that PTEN inhibits key proliferative and survival signals mediated by signalling through the PI 3-kinase/Akt(PKB) pathway (Leslie and Downes, 2002; Salmena et al, 2008). PTEN is formed from a 186 amino-acid N-terminal domain that contributes the lipid and protein phosphatase activities together with a 217 amino-acid C-terminal domain (Figure 1A). This encompasses a 166 amino-acid C2 domain able to bind PIP2 in a Ca -independent manner; a PDZ protein–protein interaction domain; a PEST motif whose modification can target PTEN for degradation and, additionally, a region undergoing multisite phosphorylation that provides a potential regulatory role. The importance of the C-terminal portion of PTEN is exemplified by the fact that nearly half of the PTEN mutations found in various cancers locate to this region. This multidomain structure allows PTEN to regulate major cellular functions not only via its lipid phosphatase activity