title: SLP-65 regulates immunoglobulin light chain gene recombination through the PI(3)K-PKB-Foxo pathway.
abstract: Although the essential role of the adaptor protein SLP-65 in pre-B cell differentiation is established, the molecular mechanism underlying its function is poorly understood. In this study, we uncover a link between SLP-65-dependent signaling and the phosphoinositide-3-OH kinase (PI(3)K)-protein kinase B (PKB)-Foxo pathway. We show that the forkhead box transcription factor Foxo3a promotes light chain rearrangement in pre-B cells. Our data suggest that PKB suppresses light chain recombination by phosphorylating Foxo proteins, whereas reconstitution of SLP-65 function counteracts PKB activation and promotes Foxo3a and Foxo1 activity in pre-B cells. Together, these data illuminate a molecular function of SLP-65 and identify a key role for Foxo proteins in the regulation of light chain recombination, receptor editing and B cell selection.
authors.affiliation: Max Planck Institute for Immunobiology, 79108 Freiburg, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Herzog
authors.forename: Eva
authors.initials: E
authors.lastname: Hug
authors.forename: Sonja
authors.initials: S
authors.lastname: Meixlsperger
authors.forename: Ji-Hye
authors.initials: JH
authors.lastname: Paik
authors.forename: Ronald A
authors.initials: RA
authors.lastname: DePinho
authors.forename: Michael
authors.initials: M
authors.lastname: Reth
authors.forename: Hassan
authors.initials: H
authors.lastname: Jumaa
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D051858:Forkhead Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D050439:Genes, Immunoglobulin Light Chain / Q000235:genetics*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011995:Recombination, Genetic
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D051858:Forkhead Transcription Factors; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases