Editors' ChoiceCell Biology

PTEN Under Arrest

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Science Signaling  12 Jul 2011:
Vol. 4, Issue 181, pp. ec193
DOI: 10.1126/scisignal.4181ec193

The lipid phosphatase PTEN converts phosphatidylinositol 3,4,5 trisphosphate (PIP3) to PIP2, thereby inhibiting mitogenic signaling mediated by phosphatidylinosinol 3-kinase (PI3K) and downstream effectors such as Akt. Lima-Fernandes et al. (see also the commentary by Houslay) identified the adapter protein β-arrestin as a binding partner for PTEN. This interaction was direct, required the C2 domain of PTEN, and activated the lipid phosphatase activity of PTEN in vitro. The guanosine triphosphatase RhoA activates the lipid phosphatase activity of PTEN, and the authors found that this effect required β-arrestin. Manipulations that increased or decreased the activity of RhoA enhanced or reduced the association of PTEN with β-arrestin, respectively. Furthermore, the RhoA effector ROCK was a component in the PTEN-β-arrestin complex. Stimulation of transfected lysophosphatidic acid receptor 1 (LPA1-R), a G protein–coupled receptor that activates RhoA, increased the association of PTEN with β-arrestin and induced translocation of the complex to the plasma membrane. In PTEN-null PC-3 prostate cancer cells, phosphorylation, and thus activation, of Akt was inhibited by reconstitution with PTEN, an effect that was potentiated by coexpression of β-arrestin1 or β-arrestin2. This potentiation required the lipid phosphatase activity of PTEN. In wild-type mouse embryonic fibroblasts (MEFs), stimulation of endogenous LPA-R elicited an increase in Akt phosphorylation that peaked and then returned to baseline, whereas in MEFs deficient in both β-arrestins (DKO MEFs), Akt phosphorylation peaked and did not return to baseline. In addition, DKO MEFs proliferated faster than did wild-type MEFs, a phenotype that was rescued by reconstitution of DKO MEFs with β-arrestin1. The C2 domain of PTEN inhibits migration of glioma cells, a function that is independent of the lipid phosphatase activity of PTEN. In U373 glioma cells (which are PTEN null) reconstituted with PTEN, the association of PTEN with exogenous β-arrestin1 was increased after wounding and during migration. U373 cells expressing only PTEN failed to migrate after wounding, an effect rescued by coexpression of a β-arrestin. The ability of β-arrestin to alleviate the inhibitory effects of PTEN on migration required the protein phosphatase activity of PTEN. Thus, β-arrestin activates the lipid phosphatase activity of PTEN to enhance its antiproliferative effects mediated by its inhibition of the PI3K-Akt pathway and inhibits the lipid phosphatase-independent function of PTEN in cell migration.

E. Lima-Fernandes, H. Enslen, E. Camand, L. Kotelevets, C. Boularan, L. Achour, A. Benmerah, L. C. D. Gibson, G. S. Baillie, J. A. Pitcher, E. Chastre, S. Etienne-Manneville, S. Marullo, M. G. H. Scott, Distinct functional outputs of PTEN signalling are controlled by dynamic association with β-arrestins. EMBO J. 30, 2557–2568 (2011). [PubMed]

M. D. Houslay, Arresting times for PTEN. EMBO J. 30, 2513–2515 (2011). [PubMed]

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