Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Sci Adv 2018 Jan;4(1):eaar5701
Date
02/06/2018Pubmed ID
29399633Pubmed Central ID
PMC5792226DOI
10.1126/sciadv.aar5701Scopus ID
2-s2.0-85042155531 (requires institutional sign-in at Scopus site) 30 CitationsAbstract
Interleukin-7 (IL-7) drives early B lymphopoiesis, but the underlying molecular circuits remain poorly understood, especially how Stat5 (signal transducer and activator of transcription 5)-dependent and Stat5-independent pathways contribute to this process. Combining transcriptome and proteome analyses and mouse genetic models, we show that IL-7 promotes anabolic metabolism and biosynthetic programs in pro-B cells. IL-7-mediated activation of mTORC1 (mechanistic target of rapamycin complex 1) supported cell proliferation and metabolism in a Stat5-independent, Myc-dependent manner but was largely dispensable for cell survival or Rag1 and Rag2 gene expression. mTORC1 was also required for Myc-driven lymphomagenesis. PI3K (phosphatidylinositol 3-kinase) and mTORC1 had discrete effects on Stat5 signaling and independently controlled B cell development. PI3K was actively suppressed by PTEN (phosphatase and tensin homolog) in pro-B cells to ensure proper IL-7R expression, Stat5 activation, heavy chain rearrangement, and cell survival, suggesting the unexpected bifurcation of the classical PI3K-mTOR signaling. Together, our integrative analyses establish IL-7R-mTORC1-Myc and PTEN-mediated PI3K suppression as discrete signaling axes driving B cell development, with differential effects on IL-7R-Stat5 signaling.
Author List
Zeng H, Yu M, Tan H, Li Y, Su W, Shi H, Dhungana Y, Guy C, Neale G, Cloer C, Peng J, Wang D, Chi HAuthor
Demin Wang PhD Professor in the Microbiology and Immunology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsB-Lymphocytes
Cell Differentiation
Cell Survival
Forkhead Box Protein O1
Gene Rearrangement
Interleukin-7
Lymphoma, B-Cell
Lymphopoiesis
Mechanistic Target of Rapamycin Complex 1
Mechanistic Target of Rapamycin Complex 2
Mice, Inbred C57BL
PTEN Phosphohydrolase
Phosphatidylinositol 3-Kinases
Protein Biosynthesis
Proto-Oncogene Proteins c-myc
Receptors, Interleukin-7
STAT5 Transcription Factor
Signal Transduction
Transcription, Genetic