Phosphatase Subfamily MTMR6

Phosphatase Classification: FoldCC1: Superfamily CC1: Family Myotubularin: Subfamily MTMR6

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Evolution

MTMR6 subfamily is found throughout holozoan. Human and most if not all vertebrates has three members per genome: MTMR6, MTMR7 and MTMR8. Other metazoan such as fruit fly and C elegans has a single member.

Domain Structure

MTMR6 subfamily has three domains: PH/GRAM, phosphatase domain and coiled-coil domain. Coiled-coil domain has been shown to mediate the interaction with MTMR9 in human [1, 2, 3]. The GRAM domain is similar to PH domain in structure and is found in membrane-associated proteins. As shown in MTMR3 subfamily, PH/GRAM domain can bind to phosphoinositide lipids. But, in the case of human MTMR6, small GTPase Rab1B interacts with MTMR6 via PH/GRAM domain, and therefore regulates cellular localization in the early secretory and autophagic pathways [4].

Catalytic activity and functions

The enzymatic activity of all three human MTMR6s are up-regulated by pseudophosphatase MTMR9 through protein interactions [1, 2, 3]. The interaction between MTMR9 and MTMR6 subfamily is also observed in C elegans [5].

Though all of MTMR6, MTMR7 and MTMR8 are 3-phosphatase, they have different preferences of substrates. MTMR6/R9 complex that regulates PtdIns (3, 5)P2 levels and thereby affects apoptosis; MTMR8/R9 complex down-regulates the levels of PthIns(3)P and blocks the autophagic process [2, 3]; MTMR7/MTMR9 dephosphorylates phosphatidylinositol 3-phosphate and Ins(1,3)P2 in neuronal cells [1].

By regulating the levels of different phosphoinositides, MTMR6 subfamily is involved in various processes. For example, MTMR6 is a negative-regulator of the Ca2+-Activated K+ Channel KCa3.1 [6]. MTMR7 has also been reported to regulate T-cell differentiation and Protein kinase B AKT signaling, possibly through regulation of phosphatidylinositol [3,4,5]-trisphosphate activity [7].

References

1. Mochizuki Y and Majerus PW. Characterization of myotubularin-related protein 7 and its binding partner, myotubularin-related protein 9. Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):9768-73. DOI:10.1073/pnas.1333958100 |
2. Zou J, Chang SC, Marjanovic J, and Majerus PW. MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis. J Biol Chem. 2009 Jan 23;284(4):2064-71. DOI:10.1074/jbc.M804292200 |
3. Zou J, Zhang C, Marjanovic J, Kisseleva MV, Majerus PW, and Wilson MP. Myotubularin-related protein (MTMR) 9 determines the enzymatic activity, substrate specificity, and role in autophagy of MTMR8. Proc Natl Acad Sci U S A. 2012 Jun 12;109(24):9539-44. DOI:10.1073/pnas.1207021109 |
4. Mochizuki Y, Ohashi R, Kawamura T, Iwanari H, Kodama T, Naito M, and Hamakubo T. Phosphatidylinositol 3-phosphatase myotubularin-related protein 6 (MTMR6) is regulated by small GTPase Rab1B in the early secretory and autophagic pathways. J Biol Chem. 2013 Jan 11;288(2):1009-21. DOI:10.1074/jbc.M112.395087 |
5. Silhankova M, Port F, Harterink M, Basler K, and Korswagen HC. Wnt signalling requires MTM-6 and MTM-9 myotubularin lipid-phosphatase function in Wnt-producing cells. EMBO J. 2010 Dec 15;29(24):4094-105. DOI:10.1038/emboj.2010.278 |
6. Srivastava S, Li Z, Lin L, Liu G, Ko K, Coetzee WA, and Skolnik EY. The phosphatidylinositol 3-phosphate phosphatase myotubularin- related protein 6 (MTMR6) is a negative regulator of the Ca2+-activated K+ channel KCa3.1. Mol Cell Biol. 2005 May;25(9):3630-8. DOI:10.1128/MCB.25.9.3630-3638.2005 |
7. Guo L, Martens C, Bruno D, Porcella SF, Yamane H, Caucheteux SM, Zhu J, and Paul WE. Lipid phosphatases identified by screening a mouse phosphatase shRNA library regulate T-cell differentiation and protein kinase B AKT signaling. Proc Natl Acad Sci U S A. 2013 May 14;110(20):E1849-56. DOI:10.1073/pnas.1305070110 |