In response to stimuli, the phosphoinositide profile is regulated by phospholipases, lipid kinases, and phosphatases. Inositol lipids play important roles in a variety of intracellular signaling pathways. Consequentially, the MTMR6/R9 complex serves to inhibit stress-induced apoptosis and the MTMR8/R9 complex inhibits autophagy. In cells, the MTMR6/R9 complex significantly increases the cellular levels of PtdIns(5)P, the product of PI(3,5)P 2 dephosphorylation, whereas the MTMR8/R9 complex reduces cellular PtdIns(3)P levels. In contrast, MTMR9 increased the activity of MTMR8 by 1.4-fold and 4-fold toward PtdIns(3,5)P 2 and PtdIns(3)P, respectively. MTMR9 increased the enzymatic activity of MTMR6 toward PtdIns(3,5)P 2 by over 30-fold, and enhanced the activity toward PtdIns(3)P by only 2-fold. Complex formation between the active myotubularins and MTMR9 increases their catalytic activity and alters their substrate specificity, wherein the MTMR6/R9 complex prefers PtdIns(3,5)P 2 as substrate the MTMR8/R9 complex prefers PtdIns(3)P. We studied a subfamily of homologous myotubularins, including myotubularin-related protein 6 (MTMR6), MTMR7, and MTMR8, all of which dimerize with the catalytically inactive MTMR9. Seven members are inactive because they lack the conserved cysteine residue in the CX 5R motif required for activity. The myotubularin family consists of 16 different proteins, 9 members of which possess catalytic activity, dephosphorylating phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate at the D-3 position.

The myotubularins are a large family of inositol polyphosphate 3-phosphatases that, despite having common substrates, subsume unique functions in cells that are disparate.

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