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Discrete roles and bifurcation of PTEN signaling and mTORC1-mediated anabolic metabolism underlie IL-7-driven B lymphopoiesis. Sci Adv 2018 01;4(1):eaar5701

Date

02/06/2018

Pubmed ID

29399633

Pubmed Central ID

PMC5792226

DOI

10.1126/sciadv.aar5701

Scopus ID

2-s2.0-85042155531   4 Citations

Abstract

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 and 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 H

Author

Demin Wang PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
B-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
jenkins-FCD Prod-411 e00897e83867fcfa48419861683711f8d99adb75