Emerging studies highlight the import-ance of metabolic reprogramming in T cell development and function, although how these processes are regulated remains to be fully understood. Recent advances in dissecting the ro...Emerging studies highlight the import-ance of metabolic reprogramming in T cell development and function, although how these processes are regulated remains to be fully understood. Recent advances in dissecting the roles of Sinl-m T0RC2 signaling in early thymocyte development provide new in sight into the dynamic in terplay between immune signaling and cell metabolism, as well as the crucial role in directi ng thymocyte pro life ration and development.展开更多
Mammalian target of rapamycin complex 2(mTORC2)is a key downstream mediator of phosphoinositol-3-kinase(PI3K)dependent growth factor signaling.In lymphocytes,mTORC2 has emerged as an important regulator of cell develo...Mammalian target of rapamycin complex 2(mTORC2)is a key downstream mediator of phosphoinositol-3-kinase(PI3K)dependent growth factor signaling.In lymphocytes,mTORC2 has emerged as an important regulator of cell development,homeostasis and immune responses.However,our current understanding of mTORC2 functions and the molecular mechanisms regulating mTORC2 signaling in B and T cells are still largely incomplete.Recent studies have begun to shed light on this important pathway.We have previously reported that mTORC2 mediates growth factor dependent phosphorylation of Akt and facilitates Akt dependent phosphorylation and inactivation of transcription factors FoxO1 and FoxO3a.We have recently explored the functions of mTORC2 in B cells and show that mTORC2 plays a key role in regulating survival and immunoglobulin(Ig)gene recombination of bone marrow B cells through an Akt2-FoxO1 dependent mechanism.Ig recombination is suppressed in proliferating B cells to ensure that DNA double strand breaks are not generated in actively dividing cells.Our results raise the possibility that genetic or pharmacologic inhibition of mTORC2 may promote B cell tumor development as a result of inefficient suppression of Ig recombination in dividing B cells.We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability.展开更多
文摘Emerging studies highlight the import-ance of metabolic reprogramming in T cell development and function, although how these processes are regulated remains to be fully understood. Recent advances in dissecting the roles of Sinl-m T0RC2 signaling in early thymocyte development provide new in sight into the dynamic in terplay between immune signaling and cell metabolism, as well as the crucial role in directi ng thymocyte pro life ration and development.
基金supported in part by grant AI 063348(NIH)and PR093728(DOD)(to B.S.).
文摘Mammalian target of rapamycin complex 2(mTORC2)is a key downstream mediator of phosphoinositol-3-kinase(PI3K)dependent growth factor signaling.In lymphocytes,mTORC2 has emerged as an important regulator of cell development,homeostasis and immune responses.However,our current understanding of mTORC2 functions and the molecular mechanisms regulating mTORC2 signaling in B and T cells are still largely incomplete.Recent studies have begun to shed light on this important pathway.We have previously reported that mTORC2 mediates growth factor dependent phosphorylation of Akt and facilitates Akt dependent phosphorylation and inactivation of transcription factors FoxO1 and FoxO3a.We have recently explored the functions of mTORC2 in B cells and show that mTORC2 plays a key role in regulating survival and immunoglobulin(Ig)gene recombination of bone marrow B cells through an Akt2-FoxO1 dependent mechanism.Ig recombination is suppressed in proliferating B cells to ensure that DNA double strand breaks are not generated in actively dividing cells.Our results raise the possibility that genetic or pharmacologic inhibition of mTORC2 may promote B cell tumor development as a result of inefficient suppression of Ig recombination in dividing B cells.We also propose a novel strategy to treat cancers based on our recent discovery that mTORC2 regulates Akt protein stability.
