A unified nomenclature and amino acid numbering for human PTEN

Abstract

The tumor suppressor PTEN is a major brake for cell transformation, mainly due to its phosphatidylinositol 3,4,5-trisphosphate [PI(3,4,5)P3] phosphatase activity that directly counteracts the oncogenicity of phosphoinositide 3-kinase (PI3K). PTEN mutations are frequent in tumors and in the germ line of patients with tumor predisposition or with neurological or cognitive disorders, which makes the PTEN gene and protein a major focus of interest in current biomedical research. After almost two decades of intense investigation on the 403-residue-long PTEN protein, a previously uncharacterized form of PTEN has been discovered that contains 173 amino-terminal extra amino acids, as a result of an alternate translation initiation site. To facilitate research in the field and to avoid ambiguities in the naming and identification of PTEN amino acids from publications and databases, we propose here a unifying nomenclature and amino acid numbering for this longer form of PTEN.

Fig. 1. A nomenclature for PTEN-L amino acid numbering

(A) Schematic of human PTEN and PTEN-L and the proposed numbering of amino acids. The domains common to PTEN and PTEN-L are indicated at the top, and the amino acids flanking the domains are indicated below each protein depiction. C124 (PTEN) or C297-L (PTEN-L) corresponds to the catalytic Cys. The N- and C-terminal tails from PTEN, and the PTEN-L–specific region (residues L1-L to D173-L) are intrinsically disordered regions. The black box at the N terminus of PTEN-L corresponds to a predicted secretion signal (predicted cleavage site at amino acid S22-L). PBM, PI(4,5)P₂-binding motif; NLS, nuclear localization sequence; CLS, cytoplasmic localization sequence; PDZ-BM, PDZ-binding motif. Numbers at the bottom correspond to exon numbering. (B) Examples of nomenclature for commonly used PTEN mutations totally or partially defective for phosphatase activity (–27). (C) Examples of nomenclature for identified PTEN mutations targeting PTEN-L–specific amino acids. Loss of function has been experimentally observed for mutations A99T-L, H122Y-L, and R170G-L [(11); note that in reference (11) the amino acid numbering is one unit less]. *Reported as polymorphisms (15, 17). HNSCC, head and neck squamous cell carcinoma; LBCL, large B cell lymphoma; GBM, glioblastoma multiforme. (D) Examples of nomenclature for PTEN dimers. Examples are provided of different combinations of PTEN and PTEN-L wild-type and mutated homodimers and heterodimers. PTEN:PTEN homodimers (14) and PTEN:PTEN-L heterodimers (12) have been demonstrated experimentally. The possibility also exists of dimers containing two mutated proteins (with the same mutation or different mutations).