Fig. 7.

Functional relevance of PTEN and its proteoforms. PTEN and its translational variants give rise to various proteoforms that localize to various sub-cellular compartments to regulate cell signaling. PTEN exerts its effects on the cell cycle, ribosome biogenesis, DNA damage, and repair processes in the nucleus and nucleolus. PTEN-L and -M have putative nuclear and nucleolar localization sequences and their unique roles in these compartments remain to be determined. PTEN and PTEN-L also localize to the mitochondria where they regulate apoptosis and mitochondrial energetics, respectively. Both PTEN and PTEN-L associate with the membrane and PTEN-L has an additional membrane-binding helix that facilitates this association. The other PTEN translational variants, PTEN-M, -N, and -O also possess the membrane-binding helix and whether they truly localize to the plasma membrane is unknown. PTEN-L has also been found in extracellular tissues and in circulation in the blood stream. PTEN-L, by virtue of a cell-penetrating polyarginine peptide, re-enters the cells to inhibit PI3K signaling and has been shown to be therapeutically effective in mouse models. Whether, PTEN-L is truly secretory remains controversial. However, the biochemical process underlying its secretion represents an active area of research