Phosphatase Subfamily MTMR3

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Phosphatase Classification: Fold CC1: Superfamily CC1: Family Myotubularin: Subfamily MTMR3

MTMR3 is an inositol lipid 3-phosphatase. It is probably a protein phosphatase of receptor-regulated SMAD.


MTMR3 is a metazoan phosphatase, with two human members (MTMR3 and MTMR4) and single copies in Drosophila and C. elegans.

Domain Structure

The MTMR3 subfamily has a conserved domain combination: a divergent PH/GRAM domain, an active phosphatase domain and an atypical FYVE domain. It has been shown that the FYVE domain of MTMR3 is atypical in that it neither confers endosomal localisation nor binds to the lipid PtdIns3P. Furthermore it is not required for in vitro enzyme activity of MTMR3. In contrast, the PH/GRAM domain is able to bind to phosphoinositide lipids [1].

Catalytic activity and functions

Mammal MTMR3

Human MTMR3 is an inositol lipid 3-phosphatase, with a so-far-unique substrate specificity. It is able to hydrolyze PtdIns3P and PtdIns(3,5)P2, both in vitro and when heterologously expressed in S. cerevisiae. Thus, MTMR3 plays critical role in the cellular production of PtdIns5P [2].

MTMR3 risk polymorphism (rs713875), associated with Inflammatory bowel disease (IBD), increases MTMR3 expression, enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation [3].

Mammal MTMR4

Human MTMR4 is also an inositol lipid 3-phosphatase, with amino acid sequence identity about ~47% [4]. More recently, human MTMR4 has been reported to dephosphorylate receptor-regulated SMAD proteins [5, 6]. Ectopic expression of human MTMR4 or the single Drosophila MTMR3, CG3632, genetically interacted with Bone morphogenetic proteins (BMP) signaling axis in regulation of the vein development of Drosophila wings [6].

Related Kinases

See PI3K.


  1. Lorenzo O, Urbé S, and Clague MJ. Analysis of phosphoinositide binding domain properties within the myotubularin-related protein MTMR3. J Cell Sci. 2005 May 1;118(Pt 9):2005-12. DOI:10.1242/jcs.02325 | PubMed ID:15840652 | HubMed [Lorenzo05]
  2. Walker DM, Urbé S, Dove SK, Tenza D, Raposo G, and Clague MJ. Characterization of MTMR3. an inositol lipid 3-phosphatase with novel substrate specificity. Curr Biol. 2001 Oct 16;11(20):1600-5. DOI:10.1016/s0960-9822(01)00501-2 | PubMed ID:11676921 | HubMed [walker01]
  3. Lahiri A, Hedl M, and Abraham C. MTMR3 risk allele enhances innate receptor-induced signaling and cytokines by decreasing autophagy and increasing caspase-1 activation. Proc Natl Acad Sci U S A. 2015 Aug 18;112(33):10461-6. DOI:10.1073/pnas.1501752112 | PubMed ID:26240347 | HubMed [Lahiri15]
  4. Zhao R, Qi Y, Chen J, and Zhao ZJ. FYVE-DSP2, a FYVE domain-containing dual specificity protein phosphatase that dephosphorylates phosphotidylinositol 3-phosphate. Exp Cell Res. 2001 May 1;265(2):329-38. DOI:10.1006/excr.2001.5185 | PubMed ID:11302699 | HubMed [zhao01]
  5. Yu J, Pan L, Qin X, Chen H, Xu Y, Chen Y, and Tang H. MTMR4 attenuates transforming growth factor beta (TGFbeta) signaling by dephosphorylating R-Smads in endosomes. J Biol Chem. 2010 Mar 12;285(11):8454-62. DOI:10.1074/jbc.M109.075036 | PubMed ID:20061380 | HubMed [yu10]
  6. Yu J, He X, Chen YG, Hao Y, Yang S, Wang L, Pan L, and Tang H. Myotubularin-related protein 4 (MTMR4) attenuates BMP/Dpp signaling by dephosphorylation of Smad proteins. J Biol Chem. 2013 Jan 4;288(1):79-88. DOI:10.1074/jbc.M112.413856 | PubMed ID:23150675 | HubMed [yu13]
All Medline abstracts: PubMed | HubMed