Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2 beta in a myotubular myopathy model

X-linked centronuclear myopathy (XLCNM) is a severe human disease without existing therapies caused by mutations in the phosphoinositide 3-phosphatase MTM1. Loss of MTM1 function is associated with muscle fiber defects characterized by impaired localization of beta-integrins and other components of focal adhesions. Here we show that defective focal adhesions and reduced active beta-integrin surface levels in a cellular model of XLCNM are rescued by loss of phosphatidylinositiol 3-kinase C2 beta (PI3KC2 beta) function. Inactivation of the Mtm1 gene impaired myoblast differentiation into myotubes and resulted in reduced surface levels of active beta 1-integrins as well as corresponding defects in focal adhesions. These phenotypes were rescued by concomi-tant genetic loss of Pik3c2b or pharmacological inhibition of PI3KC2 beta activity. We further demonstrate that a hitherto unknown role of PI3KC2 beta in the endocytic traffick-ing of active beta 1-integrins rather than rescue of phosphatidylinositol 3-phosphate levels underlies the ability of Pik3c2b to act as a genetic modifier of cellular XLCNM phenotypes. Our findings reveal a crucial antagonistic function of MTM1 and PI3KC2 beta in the control of active beta-integrin surface levels, thereby providing a molecular mechanism for the adhesion and myofiber defects observed in XLCNM. They further suggest specific pharmacological inhibition of PI3KC2 beta catalysis as a viable treatment option for XLCNM patients.