Phosphatase Subfamily VSP

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Phosphatase Classification: Superfamily CC1: Family PTEN: Subfamily VSP

VSP is a transmembrane protein with a lipid phosphatase that is activated by a voltage sensor and controls activity of ion channels.

Evolution

VSPs are holozoan-specific and lost in insects and nematodes (but found in arachnids). There are two human genes, TPTE (PTEN2) and TPTE2 (TPIP). TPTE is a primate-specific duplicate of the TPTE2 locus (found in human and Gorilla, but not in chimp) There are 7 subfamily pseudogenes, some of which are expressed in testis and other selected tissues. At least one of these is conserved as far as to orangutan, and TPTE2P1 has been reported to have a role in migration of gallbladder cancer cells [1].

Domain Structure

VSPs consist of an N-terminal voltage sensor with four transmembrane regions, followed by a phosphatase domain and a C2 domain. The C2 domain modulates VSP's function by interacting with the membrane [2].

Functions

Both human genes are testis specific (GTEx: TPTE, TPTE2), though some expression in brain and stomach has been reported. The single mouse gene is localized to the Golgi apparatus [3], while TPTE has been reported to be on the plasma membrane, while splice variants of TPTE2 are found in the ER or in the cytoplasm [4].

TPTE is predicted to be catalytically inactive, and TPTE2 has been shown to have phosphoinositide 3-phosphatase activity [4].

The Ciona homolog, Ci-VSP encodes a functional voltage-sensing domain expressed in sperm, and transduces membrane depolarization into alteration of phosphoinositide levels [5]. Ci-VSP has phosphatase activity against PI(3,4,5)P3 and PI(4,5)P2 [6]. The PI(4,5)P2 activity is not seen in PTEN, and change in levels of PI(4,5)P2 affects the activity of a family of potassium channels. CI-VSP has also been seen expressed in stomach and blood cells [7].


References

  1. Lv W, Wang L, Lu J, Mu J, Liu Y, and Dong P. Downregulation of TPTE2P1 Inhibits Migration and Invasion of Gallbladder Cancer Cells. Chem Biol Drug Des. 2015 Oct;86(4):656-62. DOI:10.1111/cbdd.12533 | PubMed ID:25676706 | HubMed [Lv]
  2. Castle PM, Zolman KD, and Kohout SC. Voltage-sensing phosphatase modulation by a C2 domain. Front Pharmacol. 2015;6:63. DOI:10.3389/fphar.2015.00063 | PubMed ID:25904865 | HubMed [Castle15]
  3. Guipponi M, Tapparel C, Jousson O, Scamuffa N, Mas C, Rossier C, Hutter P, Meda P, Lyle R, Reymond A, and Antonarakis SE. The murine orthologue of the Golgi-localized TPTE protein provides clues to the evolutionary history of the human TPTE gene family. Hum Genet. 2001 Dec;109(6):569-75. DOI:10.1007/s004390100607 | PubMed ID:11810268 | HubMed [Guipponi]
  4. Walker SM, Downes CP, and Leslie NR. TPIP: a novel phosphoinositide 3-phosphatase. Biochem J. 2001 Dec 1;360(Pt 2):277-83. PubMed ID:11716755 | HubMed [Walker]
  5. Murata Y, Iwasaki H, Sasaki M, Inaba K, and Okamura Y. Phosphoinositide phosphatase activity coupled to an intrinsic voltage sensor. Nature. 2005 Jun 30;435(7046):1239-43. DOI:10.1038/nature03650 | PubMed ID:15902207 | HubMed [Murata]
  6. Iwasaki H, Murata Y, Kim Y, Hossain MI, Worby CA, Dixon JE, McCormack T, Sasaki T, and Okamura Y. A voltage-sensing phosphatase, Ci-VSP, which shares sequence identity with PTEN, dephosphorylates phosphatidylinositol 4,5-bisphosphate. Proc Natl Acad Sci U S A. 2008 Jun 10;105(23):7970-5. DOI:10.1073/pnas.0803936105 | PubMed ID:18524949 | HubMed [Iwasaki]
  7. Ogasawara M, Sasaki M, Nakazawa N, Nishino A, and Okamura Y. Gene expression profile of Ci-VSP in juveniles and adult blood cells of ascidian. Gene Expr Patterns. 2011 Mar-Apr;11(3-4):233-8. DOI:10.1016/j.gep.2010.12.004 | PubMed ID:21172457 | HubMed [Ogasawara]
All Medline abstracts: PubMed | HubMed