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Differential phosphorylation of the phosphoinositide 3-phosphatase MTMR2 regulates its association with early endosomal subtypes

Franklin, Norah E., Bonham, Christopher A., Xhabija, Besa, Vacratsis, Panayiotis O.·2013·Journal of Cell Science
DOI 10.1242/jcs.113928
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Abstract

Myotubularin-related 2 (MTMR2) is a 3-phosphoinositide lipid phosphatase with specificity towards the D-3 position of phosphoinositol 3-phosphate (PI(3)P) and phosphoinositol 3,5-bisphosphate lipids enriched on endosomal structures. Recently we have shown that phosphorylation of MTMR2 on Ser58 is responsible for its cytoplasmic sequestration while a phosphorylation deficient variant (S58A) targets MTMR2 to Rab5-positive endosomes resulting in PI(3)P depletion and an increase in endosomal signaling, including a significant increase in ERK1/2 activation. Using in vitro kinase assays, cellular MAPK inhibitors, siRNA knockdown, and a phosphospecific-Ser58 antibody, we now provide evidence that ERK1/2 is the kinase responsible for phosphorylating MTMR2 at position Ser58 suggesting that the endosomal targeting of MTMR2 is regulated through an ERK1/2 negative feedback mechanism. Surprisingly, treatment with multiple MAPK inhibitors resulted in a MTMR2 localization shift from Rab5-positive endosomes to the more proximal APPL1-positive endosomes. This MTMR2 localization shift was recapitulated when a double phosphorylation-deficient mutant (MTMR2 S58A/S631A) was characterized. Moreover, expression of this double phosphorylation-deficient MTMR2 variant led to a more sustained and pronounced increase in ERK1/2 activation compared to MTMR2 S58A. Further analysis of combinatorial phospho-mimetic mutants demonstrated it is the phosphorylation status of Ser58 that regulates general endosomal binding, while the phosphorylation status of Ser631 mediates the endosomal shuttling between Rab5 and APPL1 subtypes. Taken together these results reveal that MTMR2 compartmentalization and potential subsequent effects on endosome maturation and endosome signaling is dynamically regulated through MAPK-mediated differential phosphorylation events.

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Metadata

Authors
Franklin, N. E., Bonham, C. A., Xhabija, B., & Vacratsis, P. O.
Venue
Journal of Cell Science
Publisher
The Company of Biologists
Published
2013-01-01
ISSN
  • 1477-9137
  • 0021-9533
DOI
10.1242/jcs.113928
Cited by
8
References
2
Language
en

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