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First published online 20 June 2006
doi: 10.1242/jcs.03040

Journal of Cell Science 119, 2953-2959 (2006)
Published by The Company of Biologists 2006
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Research Article

Systematic analysis of myotubularins: heteromeric interactions, subcellular localisation and endosomerelated functions

Óscar Lorenzo, Sylvie Urbé and Michael J. Clague*

Physiological Laboratory, University of Liverpool, Crown Street, Liverpool, L69 3BX, UK

* Author for correspondence (e-mail: clague{at}liv.ac.uk)

Accepted 3 May 2005

The myotubularins are a large family of lipid phosphatases with specificity towards PtdIns3P and PtdIns(3,5)P2. Each of the 14 family members bears a signature phosphatase domain, which is inactive in six cases due to amino acid changes at the catalytic site. Fragmentary data have indicated heteromeric interactions between myotubularins, which have hitherto paired an active family member with an inactive one. In this study we have conducted a largescale analysis of potential associations within the human myotubularin family, through directed two-hybrid screening and immunoprecipitation of epitope-tagged proteins. We have confirmed all previously reported combinations and identified novel heteromeric interactions: MTMR8 with MTMR9, and MTMR3 with MTMR4, the first such combination of enzymatically active MTMs. We also report the capacity of several family members to self-associate, including MTMR3 and MTMR4. Subcellular localisation studies reveal a unique distribution of MTMR4 to endosomal structures, the major site of substrate lipid accumulation. All active MTMs we have tested (MTM1, MTMR2-MTMR4) reduce endosomal PtdIns3P levels upon overexpression. Despite this, only MTMR4 exerts any effect on EGF receptor trafficking and degradation, which is more pronounced with a phosphatase inactive form of MTMR4 and requires an intact FYVE domain.

Key words: Myotubularin, Phosphatase, Yeast two-hybrid, Proteinprotein interactions, Endosomes


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