Phosphatase Subfamily PTEN

Phosphatase Classification: Superfamily CC1: Family PTEN: Subfamily PTEN

PTEN dephosphorylates phosphatidylinositol (3,4,5)-trisphosphate (PtdIns (3,4,5)P3 or PIP3). PTEN is one of the most commonly lost tumor suppressors in human cancer.

Evolution

PTEN is found in almost all eukaryotes.

Domain

PTENs typically have a phosphatase domain followed by a C2 domain. C2 domain tethers PTEN to vesicles by specifically binding to phosphatidylinositol 3-phosphate (PI(3)P) (the signature lipid of endosomes) through the CBR3 loop [1].

The N-terminus of human PTEN contains a nuclear localization signal (NLS) (7-31), an overlapping PIP2-binding motif (PBM) (6-15) and a cytoplasmic localization signal (CLS) (19-25) (positions are numbered by human PTEN) [2].

Fungal loss of C2 domain

The C2 domain is lost from all fungi, including S. cerevisiae TEP1, though it still functions as a PTEN [3]. The C2 domain is present in animals, Dictyostelium, and other basal eukaryotes (see technical notes). Some fungal homologs have PH (phospholipid-binding) or LIM domains.

Functions

PTEN is a critical negative regulator of PI3K signaling. PI3K produce the lipid second messenger phosphatidylinositol 3,4,5-trisphosphate (PI (3,4,5)) trisphosphate (PI(3,4,5)P3/PIP3) in response to activation of receptor tyrosine kinases (RTKs), G-protein-coupled receptors, or membrane-bound oncogenes [4, 5]. It dephosphorylates the lipid second messenger, PI (3,4,5) [6]. It is mostly found in the cell cytoplasm, tethered to endosome vesicles. This localization regulates the enzyme’s activity towards specific lipids and influences its control of cell growth [7].

PTEN is a tumor suppressor and among the most frequently altered genes in cancer [8, 9]. However, as opposed to its tumor suppressor role in other cancers, PTEN inhibition in pre-B ALL is therapeutically effective and triggers cell death [10].

Technical notes

Fungal loss of the C2 domain

We observed the absence of C2 domain in budding yeast and its presence in Dictystelium. We then asked i) whether C2 domain is generally absent from all fungi, ii) whether C2 domain is generally present in amoeba and/or basal eukaryotes, which means the presence of C2 domain before fungi diverged from other eukaryotes and lost C2 domain. To answer the questions, we BLASTed the sequence of the C2 domain of human PTEN (188-379) against NR dataset limiting the organisms to non-metazoa eukaryotes using NCBI BLAST server. We then manually looked through the domain combination of the hits of amoebazoa and basal eukaryotes through the link to sequence page, which has the link of conserved domain. In brief, we found, i) no hit from fungi, ii) the hits from amoebazoa and basal eukaryotes usually have the C2 domain.

References

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