MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis.
Myotubularin-related protein 6 (MTMR6) is a catalytically active member of the myotubularin (MTM) family, which is composed of 14 proteins. Catalytically active myotubularins possess 3-phosphatase activity dephosphorylating phosphatidylinositol-3-phoshate and phosphatidylinositol-3,5-bisphosphate, and some members have been shown to form homomers or heteromeric complexes with catalytically inactive myotubularins. We demonstrate that human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells. MTMR9 increased the binding of MTMR6 to phospholipids without changing the lipid binding profile. MTMR9 increased the 3-phosphatase activity of MTMR6 up to 6-fold. We determined that MTMR6 is activated up to 28-fold in the presence of phosphatidylserine liposomes. Together, MTMR6 activity in the presence of MTMR9 and assayed in phosphatidylserine liposomes increased 84-fold. Moreover, the formation of this heteromer in cells resulted in increased protein levels of both MTMR6 and MTMR9, probably due to the inhibition of degradation of both proteins. Furthermore, co-expression of MTMR6 and MTMR9 decreased etoposide-induced apoptosis, whereas decreasing both MTMR6 and MTMR9 by RNA interference led to increased cell death in response to etoposide treatment when compared with that seen with RNA interference of MTMR6 alone. Thus, MTMR9 greatly enhances the functions of MTMR6.
Zou
Jun
J
Division of Hematology, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Chang
Shao-Chun
SC
Marjanovic
Jasna
J
Majerus
Philip W
PW
D017209:Apoptosis; D055162:Biocatalysis; D004789:Enzyme Activation; D004795:Enzyme Stability; D006367:HeLa Cells; D006801:Humans; D010743:Phospholipids / Q000378:metabolism; D011485:Protein Binding; D055503:Protein Multimerization; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000235:genetics / Q000378:metabolism*
D010743:Phospholipids; C513490:MTMR6 protein, human; C435691:MTMR9 protein, human; D054558:Protein Tyrosine Phosphatases, Non-Receptor