CMT 4B: Endosomal Targeting of the Phosphoinositide 3-Phosphatase MTMR2 is Regu

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J Biol Chem. 2011 Mar 3. [Epub ahead of print]

Endosomal Targeting of the Phosphoinositide 3-Phosphatase MTMR2 is Regulated by

an N-Terminal Phosphorylation Site.

lin NE, GS, Vacratsis PO.

University of Windsor, Canada

Abstract

MTMR2 is a member of the myotubularin family of inositol lipid phosphatases, a

large protein tyrosine phosphatase subgroup that is conserved from yeast to

humans. Furthermore, the peripheral neuromuscular disease Charcot-Marie Tooth

disease type 4B has been attributed to mutations in the mtmr2 gene.

Because the molecular mechanisms regulating MTMR2 have been poorly defined, we

investigated whether reversible phosphorylation might regulate MTMR2 function.

We used mass spectrometry based methods to identify a high stoichiometry

phosphorylation site on serine 58 of MTMR2. Phosphorylation at Ser58, or a

phospho-mimetic S58E mutation, markedly decreased MTMR2 localization to

endocytic vesicular structures. In contrast, a phosphorylation-deficient MTMR2

mutant (S58A) displayed constitutive localization to early endocytic structures.

This localization pattern was accompanied by displacement of a PI(3)P-specific

sensor protein and an increase in signal transduction pathways. Thus, MTMR2

phosphorylation is likely to be a critical mechanism by which MTMR2 access to

its lipid substrate(s) is temporally and spatially regulated, thereby

contributing to the control of downstream endosome maturation events.