Phosphatase Subfamily MTMR14

Phosphatase Classification: Fold CC1: Superfamily CC1: Family Myotubularin: Subfamily MTMR14

MTMR14 is an lipid phosphatase though to act on phosphatidylinositol bisphophosphates PtdIns(3,5)P2 and PtdIns (3,4)P2.

Evolution

MTMR14 is found in most metazoa except nematodes, and in scattered protists.

Domain Structure

MTMR14 in eumetazoa has a conserved domain combination: a PH/GRAM domain and an active phosphatase domain. It may have a coiled-coil domain, but it is much weaker compared with other myotubularins using coiled-coil detection programs COILS and PAIRCOIL2. While most active myotubularins dimerize with inactive homologs through the coiled coil domain, no such inactive partner has been described for MTMR14, which may explain the weak coiled-coil score.

Choanoflagellate Monosiga has a predicted transmembrane region (see database).

Catalytic activity and functions

Human MTMR14 (JUMPY) dephosphorylates PtdIns(3,5)P2 and PtdIns (3,4)P2.

It is highly expressed in skeleton muscle and exogenous GFP-MTMR14 localizes to the Golgi apparatus in vitro [1]. Mice deficient in MTMR14 show muscle weakness and fatigue. The mechanism model behind is deficiency in MTMR14 causes accumulation of its substrates, especially PtdIns(3,5)P2 and PtdIns (3,4)P2, which bind, and directly activate, the Ca2+ release channel (ryanodine receptor 1, RyR1) of the internal store - the sarcoplasmic reticulum, and the activation of RyR1 results in the spontaneous Ca2+ leakage from the sarcoplasmic reticulum [2].

MTMR14 has also been shown to be involved in the regulation of autophagy [3, 4].

Drosophila MTMR14, EDTP (Egg-Derived Tyrosine Phosphatase) has roles in oogenesis, embryogenesis [5], and muscle aging, and its expression is induced along with several other autophagy genes during starvation [6]. Another insect homolog, from Sarcophaga peregrina, showed tyrosine phosphatase activity in vitro and was degraded by cathepsin L during embyrogenesis [7]

References

1. Tosch V, Rohde HM, Tronchère H, Zanoteli E, Monroy N, Kretz C, Dondaine N, Payrastre B, Mandel JL, and Laporte J. A novel PtdIns3P and PtdIns(3,5)P2 phosphatase with an inactivating variant in centronuclear myopathy. Hum Mol Genet. 2006 Nov 1;15(21):3098-106. DOI:10.1093/hmg/ddl250 |
2. Shen J, Yu WM, Brotto M, Scherman JA, Guo C, Stoddard C, Nosek TM, Valdivia HH, and Qu CK. Deficiency of MIP/MTMR14 phosphatase induces a muscle disorder by disrupting Ca(2+) homeostasis. Nat Cell Biol. 2009 Jun;11(6):769-76. DOI:10.1038/ncb1884 |
3. Vergne I, Roberts E, Elmaoued RA, Tosch V, Delgado MA, Proikas-Cezanne T, Laporte J, and Deretic V. Control of autophagy initiation by phosphoinositide 3-phosphatase Jumpy. EMBO J. 2009 Aug 5;28(15):2244-58. DOI:10.1038/emboj.2009.159 |
4. Gibbs EM, Feldman EL, and Dowling JJ. The role of MTMR14 in autophagy and in muscle disease. Autophagy. 2010 Aug;6(6):819-20. DOI:10.4161/auto.6.6.12624 |
5. Yamaguchi S, Katagiri S, Sekimizu K, Natori S, and Homma KJ. Involvement of EDTP, an egg-derived tyrosine phosphatase, in the early development of Drosophila melanogaster. J Biochem. 2005 Dec;138(6):721-8. DOI:10.1093/jb/mvi176 |
6. Grande M, Tucci GF, and Federico F. [A case of malignant retroperitoneal fibrohistiocytoma]. G Chir. 1989 Mar;10(3):98-102.
7. Yamaguchi S, Homma K, and Natori S. A novel egg-derived tyrosine phosphatase, EDTP, that participates in the embryogenesis of Sarcophaga peregrina (flesh fly). Eur J Biochem. 1999 Feb;259(3):946-53. DOI:10.1046/j.1432-1327.1999.00143.x |