Myotubularin and MTMR2, phosphatidylinositol 3-phosphatases mutated in myotubular myopathy and type 4B Charcot-Marie-Tooth disease.
Myotubularin is the archetype of a family of highly conserved protein-tyrosine phosphatase-like enzymes. The myotubularin gene, MTM1, is mutated in the genetic disorder, X-linked myotubular myopathy. We and others have previously shown that myotubularin utilizes the lipid second messenger, phosphatidylinositol 3-phosphate (PI(3)P), as a physiologic substrate. We demonstrate here that the myotubularin-related protein MTMR2, which is mutated in the neurodegenerative disorder, type 4B Charcot-Marie-Tooth disease, is also highly specific for PI(3)P as a substrate. Furthermore, the MTM-related phosphatases MTMR1, MTMR3, and MTMR6 also dephosphorylate PI(3)P, suggesting that activity toward this substrate is common to all myotubularin family enzymes. A direct comparison of the lipid phosphatase activities of recombinant myotubularin and MTMR2 demonstrates that their enzymatic properties are indistinguishable, indicating that the lack of functional redundancy between these proteins is likely to be due to factors other than the utilization of different physiologic substrates. To this end, we have analyzed myotubularin and MTMR2 transcripts during induced differentiation of cultured murine C2C12 myoblasts and find that their expression is divergently regulated. In addition, myotubularin and MTMR2 enhanced green fluorescent protein fusion proteins exhibit overlapping but distinct patterns of subcellular localization. Finally, we provide evidence that myotubularin, but not MTMR2, can modulate the levels of endosomal PI(3)P. From these data, we conclude that the developmental expression and subcellular localization of myotubularin and MTMR2 are differentially regulated, resulting in their utilization of specific cellular pools of PI(3)P.
Kim
Soo-A
SA
Life Sciences Institute and Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, Michigan 48109-0606, USA.
Taylor
Gregory S
GS
Torgersen
Knut M
KM
Dixon
Jack E
JE
D000818:Animals; D002460:Cell Line; D002607:Charcot-Marie-Tooth Disease / Q000235:genetics*; D006801:Humans; D008856:Microscopy, Fluorescence; D009154:Mutation; D020914:Myopathies, Structural, Congenital / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics* / Q000378:metabolism; D017027:Protein Tyrosine Phosphatases / Q000235:genetics* / Q000378:metabolism; D054558:Protein Tyrosine Phosphatases, Non-Receptor; D013347:Subcellular Fractions / Q000201:enzymology / Q000378:metabolism
D010744:Phosphoric Monoester Hydrolases; C408986:MTMR2 protein, human; D017027:Protein Tyrosine Phosphatases; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin; C061816:phosphatidylinositol-3-phosphatase