Phosphatase Subfamily PTEN
Phosphatase Classification: Superfamily CC1: Family PTEN: Subfamily PTEN
PTEN subfamily is named after its single member in human, PTEN, which 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 (see here).
The N-terminus of human PTEN contains a nuclear localization signal (NLS) (7-31), an overlapping PIP2-binding motif (PBM) (6-15) and cytoplasmic localization signal (CLS) (19-25) (positions are numbered by human PTEN) [1].
Fungi lost C2 domain
Some homologs have PH (phospholipid-binding) or LIM domains. Yeast PTEN TEP1 lacks the C2 domain, but its functions as PTEN [2]. The C2 domain is actually absent from all fungi, but present in amoeba and basal eukaryotes (see technical notes).
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 [3, 4]. It dephosphorylates the lipid second messenger, PI (3,4,5) [5]. It is tumor suppressor among the most frequently altered genes in cancer [6, 7].
References
- Gil A, Rodríguez-Escudero I, Stumpf M, Molina M, Cid VJ, and Pulido R. A functional dissection of PTEN N-terminus: implications in PTEN subcellular targeting and tumor suppressor activity. PLoS One. 2015;10(4):e0119287. DOI:10.1371/journal.pone.0119287 |
- Heymont J, Berenfeld L, Collins J, Kaganovich A, Maynes B, Moulin A, Ratskovskaya I, Poon PP, Johnston GC, Kamenetsky M, DeSilva J, Sun H, Petsko GA, and Engebrecht J. TEP1, the yeast homolog of the human tumor suppressor gene PTEN/MMAC1/TEP1, is linked to the phosphatidylinositol pathway and plays a role in the developmental process of sporulation. Proc Natl Acad Sci U S A. 2000 Nov 7;97(23):12672-7. DOI:10.1073/pnas.97.23.12672 |
- Engelman JA, Luo J, and Cantley LC. The evolution of phosphatidylinositol 3-kinases as regulators of growth and metabolism. Nat Rev Genet. 2006 Aug;7(8):606-19. DOI:10.1038/nrg1879 |
- Vanhaesebroeck B, Stephens L, and Hawkins P. PI3K signalling: the path to discovery and understanding. Nat Rev Mol Cell Biol. 2012 Feb 23;13(3):195-203. DOI:10.1038/nrm3290 |
- Maehama T and Dixon JE. The tumor suppressor, PTEN/MMAC1, dephosphorylates the lipid second messenger, phosphatidylinositol 3,4,5-trisphosphate. J Biol Chem. 1998 May 29;273(22):13375-8. DOI:10.1074/jbc.273.22.13375 |
- Li J, Yen C, Liaw D, Podsypanina K, Bose S, Wang SI, Puc J, Miliaresis C, Rodgers L, McCombie R, Bigner SH, Giovanella BC, Ittmann M, Tycko B, Hibshoosh H, Wigler MH, and Parsons R. PTEN, a putative protein tyrosine phosphatase gene mutated in human brain, breast, and prostate cancer. Science. 1997 Mar 28;275(5308):1943-7. DOI:10.1126/science.275.5308.1943 |
- Steck PA, Pershouse MA, Jasser SA, Yung WK, Lin H, Ligon AH, Langford LA, Baumgard ML, Hattier T, Davis T, Frye C, Hu R, Swedlund B, Teng DH, and Tavtigian SV. Identification of a candidate tumour suppressor gene, MMAC1, at chromosome 10q23.3 that is mutated in multiple advanced cancers. Nat Genet. 1997 Apr;15(4):356-62. DOI:10.1038/ng0497-356 |
