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These phosphoinositols mainly reside on endocytic structures and play key roles in membrane targeting, vesicular trafficking, and regulation of signal transduction pathways by interacting and recruiting distinct signaling proteins containing appropriate phosphoinositol-binding module(s) ( Balla, 2005 Cullen et al., 2001 Vanhaesebroeck et al., 2001). Taken together, these results reveal that MTMR2 compartmentalization and potential subsequent effects on endosome maturation and endosome signaling are dynamically regulated through MAPK-mediated differential phosphorylation events.Īlthough the majority of protein tyrosine phosphatases (PTPs) use phosphotyrosine-containing proteins as substrates, the active myotubularin (MTM) family members dephosphorylate the lipid second messengers phosphoinositol 3-phosphate ( Blondeau et al., 2000 Kim et al., 2002 Taylor et al., 2000 Walker et al., 2001). Further analysis of combinatorial phospho-mimetic mutants demonstrated that it is the phosphorylation status of Ser58 that regulates general endosomal binding and that the phosphorylation status of Ser631 mediates the endosomal shuttling between Rab5 and APPL1 subtypes. Moreover, expression of this double phosphorylation-deficient MTMR2 variant led to a more sustained and pronounced increase in ERK1/2 activation compared with MTMR2 S58A. This MTMR2 localization shift was recapitulated when a double phosphorylation-deficient mutant (MTMR2 S58A/S631A) was characterized. Surprisingly, treatment with multiple MAPK inhibitors resulted in a MTMR2 localization shift from Rab5-positive endosomes to the more proximal APPL1-positive endosomes. 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, which suggests that the endosomal targeting of MTMR2 is regulated through an ERK1/2 negative feedback mechanism. Recently, we have shown that phosphorylation of MTMR2 on Ser58 is responsible for its cytoplasmic sequestration and that 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.
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Myotubularin-related 2 (MTMR2) is a 3-phosphoinositide lipid phosphatase with specificity towards the D-3 position of phosphoinositol 3-phosphate and phosphoinositol 3,5-bisphosphate lipids enriched on endosomal structures.
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