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J. Biol. Chem., Vol. 280, Issue 36, 31699-31707, September 9, 2005

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The Phosphoinositide-3-phosphatase MTMR2 Associates with MTMR13, a Membrane-associated Pseudophosphatase Also Mutated in Type 4B Charcot-Marie-Tooth Disease^*

Fred L. Robinson and Jack E. Dixon¶||**

From the Departments of Pharmacology, ^¶Cellular and Molecular Medicine, and ^||Chemistry and Biochemistry, The University of California San Diego, La Jolla, California 92093

Charcot-Marie-Tooth disease type 4B (CMT4B) is a severe, demyelinating peripheral neuropathy characterized by distinctive, focally folded myelin sheaths. CMT4B is caused by recessively inherited mutations in either myotubularin-related 2 (MTMR2) or MTMR13 (also called SET-binding factor 2). MTMR2 encodes a member of the myotubularin family of phosphoinositide-3-phosphatases, which dephosphorylate phosphatidylinositol 3-phosphate (PI(3)P) and bisphosphate PI(3,5)P₂. MTMR13 encodes a large, uncharacterized member of the myotubularin family. The MTMR13 phosphatase domain is catalytically inactive because the essential Cys and Arg residues are absent. Given the genetic association of both MTMR2 and MTMR13 with CMT4B, we investigated the biochemical relationship between these two proteins. We found that the endogenous MTMR2 and MTMR13 proteins are associated in human embryonic kidney 293 cells. MTMR2-MTMR13 association is mediated by coiled-coil sequences present in each protein. We also examined the cellular localization of MTMR2 and MTMR13 using fluorescence microscopy and subcellular fractionation. We found that (i) MTMR13 is a predominantly membrane-associated protein; (ii) MTMR2 and MTMR13 cofractionate in both a light membrane fraction and a cytosolic fraction; and (iii) MTMR13 membrane association is mediated by the segment of the protein which contains the pseudophosphatase domain. This work, which describes the first cellular or biochemical investigation of the MTMR13 pseudophosphatase protein, suggests that MTMR13 functions in association with MTMR2. Loss of MTMR13 function in CMT4B2 patients may lead to alterations in MTMR2 function and subsequent alterations in 3-phosphoinositide signaling. Such a mechanism would explain the strikingly similar phenotypes of patients with recessive mutations in either MTMR2 or MTMR13.

Received for publication, May 11, 2005 , and in revised form, July 1, 2005.

^* This work was supported in part by National Institutes of Health Grant 2R01 DK018024-31 and a grant from the Walther Cancer Institute (to J. E. D.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Supported by Ruth L. Kirschstein National Research Service Award Postdoctoral Grants 5 T32 HD07203-20 and 1 F32 NS047846-01A1 from the NICHHD and NINDS, National Institutes of Health, respectively.

^** To whom correspondence should be addressed: Dept. of Pharmacology, University of California San Diego, School of Medicine, Leichtag Bldg., Rm. 284, 9500 Gilman Dr., La Jolla, CA 92093-0721. Tel.: 858-822-0491; Fax: 858-822-5888; E-mail: jedixon{at}ucsd.edu.

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