PTEN Dephosphorylates 5HT2C Receptor via Its Protein Phosphatase but Not Its Lipid Phosphatase Activity

The above results did not show, however, the detailed mechanism underlying PTEN dephosphorylation of 5-HT2C receptor. In an attempt to discover whether PTEN utilizes its protein phosphatase or lipid phosphatase to regulate 5-HT2C receptor phosphorylation, two additional types of stable PC12 cell lines were prepared. G129R, a PTEN mutant eliminating both protein and lipid phosphatase functions (Furnari et al. 1997), was overexpressed in one type of cell line. G129E, another PTEN mutant without the lipid phosphatase activity only (Myers et al. 1998), was overexpressed in the other cell line. R0600175 was able to phosphorylate 5-HT2C receptor in the G129E cells but not in G129R cells (Ji et al. 2006), indicating that PTEN dephosphorylates 5-HT2cR via its protein phosphatase but not its lipid phos-phatase activity.

Next, we examined whether disruption of protein-protein coupling between 5-HT2cR and PTEN could block the ability of PTEN to dephosphorylate phos-phorylated 5-HT2cR. In order to do so, 3L4F peptide was rendered cell permeable by fusing it to the cell-membrane transduction domain of an human immunodeficiency virus (HIV) Tat protein (YGRKKRRQRRR) to obtain the Tat-3L4F peptide. Bath application of the Tat-3L4F into wild-type PTEN-overexpressing cells before pretreatment with Ro600175 abolished the capacity of PTEN to dephosphorylate Ro600175-induced phosphorylation of 5-HT2cR (Ji et al. 2006), suggesting that the Tat-3L4F peptide is effective in blocking PTEN from dephosphorylating 5-HT2cR. Considering that a previous study (Backstrom et al. 2000) showed that the site of phosphorylation of 5-HT2cR was on its C-terminal, how PTEN dephosphorylates 5-HT2cR by binding to its third intracellular loop is not clear. One possibility is that 5-HT2C receptor may interact with PTEN through additional contacting sites on its C-terminal (Ji et al. 2006).

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