Crystal Structure of the PTEN Tumor Suppressor

Abstract

The PTEN tumor suppressor is mutated in diverse human cancers and in hereditary cancer predisposition syndromes. PTEN is a phosphatase that can act on both polypeptide and phosphoinositide substrates in vitro. The PTEN structure reveals a phosphatase domain that is similar to protein phosphatases but has an enlarged active site important for the accommodation of the phosphoinositide substrate. The structure also reveals that PTEN has a C2 domain. The PTEN C2 domain binds phospholipid membranes in vitro, and mutation of basic residues that could mediate this reduces PTEN's membrane affinity and its ability to suppress the growth of glioblastoma tumor cells. The phosphatase and C2 domains associate across an extensive interface, suggesting that the C2 domain may serve to productively position the catalytic domain on the membrane.

PTEN regulates tumor cell adhesion of colon carcinoma cells under dynamic conditions of fluid flow

“…Similar results were obtained during embryogenesis using mPTEN-de®cient mice (Stambolic et al, 1998). In addition, mutations in the basic residues of the PTEN C2-domain reduced PTEN membrane a nity and resulted in enhanced growth of glioblastoma cells (Lee et al, 1999). Mutations in this Cterminal region can also a ect PTEN stability and enzymatic phosphatase activity Leslie et al, 2000).…”

“…An analysis of the crystal structure of PTEN reveales a large pocket accommodating the phosphatase catalytic site and a C2-domain that can bind to phospholipid membranes in vitro (Lee et al, 1999). Recent studies have demostrated that PTEN can dephosphorylate PIP 3 (phosphatidylinositol 3,4,5-triphosphate), and thus it is a direct antagonist to the Dixon, 1998, 1999;Wang et al, 2000).…”

PTEN mutations are common in sporadic microsatellite stable colorectal cancer

“…Overall, the N-terminal phosphatase domain (residues 7-185) was the site of six missense and one nonsense mutation, including the K125E and K125X mutations that lie within the core phosphatase motif of PTEN and are predicted to alter at least the lipid phosphatase activity essential for PTEN tumour suppressor function (Lee et al, 1999;Han et al, 2000). Interestingly, codon 125, an invariant lysine residue, appears to be a target with two distinct mutations occurring at this site.…”

PTEN, here, there, everywhere

“…5 The C-terminal half of PTEN features a Ca 2 þ -independent C2 domain thought to mediate PTEN interactions with the plasma membrane. 6 A cluster of cationic residues of the b-sandwich, composed of eight b-strands, on the membrane-binding face of PTEN appear to mediate membrane anchoring. 6 Recent evidence suggests further complexity of these interactions, namely, that PTEN SUMOylation at K 266 located within the CBR3 loop has a central role in PTEN membrane association, facilitating the binding of PTEN to the plasma membrane via electrostatic interactions.…”

“…6 A cluster of cationic residues of the b-sandwich, composed of eight b-strands, on the membrane-binding face of PTEN appear to mediate membrane anchoring. 6 Recent evidence suggests further complexity of these interactions, namely, that PTEN SUMOylation at K 266 located within the CBR3 loop has a central role in PTEN membrane association, facilitating the binding of PTEN to the plasma membrane via electrostatic interactions. 7 However, structural analysis using neutron reflectometry challenges this model and demonstrates that the CBR3 loop of PTEN's C2 domain, as well as further electrostatic interactions of the phosphatase domain, is sufficient for membrane association, independent of SUMOylation.…”