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Regulation of PTEN Binding to MAGI-2 by Two Putative Phosphorylation Sites at Threonine 382 and 383¹

The Derald H. Ruttenberg Cancer Center, Mount Sinai School of Medicine, New York, New York 10029 [T. T., M. B., A. S., A. C. K., A. M. C.], and the Institute for Enzyme Research, University of Tokushima, Tokushima 770-8503, Japan [K. T.]

We have reported previously that the PTEN COOH-terminal 33 amino acids play a role in the maintenance of PTEN protein stability (Tolkacheva and Chan, Oncogene, 19: 680–689, 2000). By site-directed mutagenesis, we identified two threonine residues within this COOH-terminal region at codon 382 and 383 that may be targets for phosphorylation events. Interestingly, PTEN mutants rendered phosphorylation-incompetent at these two sites, T382A/T383A, and were found to have drastically reduced expression in cultured cells. The enhanced degradation of PTEN was most likely mediated by the proteosome-dependent pathway, we have evidence that PTEN was polyubiquitinated. More interestingly, the non-phosphorylated forms of PTEN displayed significantly greater binding affinity than the wild-type protein to a previously identified PTEN interacting partner, MAGI-2/ARIP1. On the basis of all these data, we propose that PTEN recruitment to the cell-cell junction may be regulated through the phosphorylation of its COOH terminus.

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