title: Broad feedback inhibition of pre-B-cell receptor signaling components.
abstract: During B lymphocyte development, first immunoglobulin heavy chain gene segments and then immunoglobulin light chain gene segments are rearranged to create antibody diversity. Early in the development, expression of a pre-B-cell receptor (pre-BCR) that has membrane-bound Ig heavy chain protein associated with surrogate light chain (SLC) proteins serves as a critical checkpoint that monitors for functional heavy chain rearrangement. Signaling from the pre-BCR induces survival and clonal expansion to select cells with good heavy chains, but it also down-regulates transcription of the genes for the SLC proteins and CD19 and limits its own proliferative signaling. Here we have analyzed whether the down-regulation is limited to the SLC proteins and CD19, and we show that the pre-BCR of primary mouse pre-B-cells instead is subject to a broad feedback inhibition of pre-BCR signaling components. Activation of signaling leads to down-regulation of the receptor proteins, many co-receptors and proteins participating in signal pathways from the receptor. Thus the down-regulation of the pre-BCR is much broader than previously assumed. We also show that Ca(2+)/calmodulin inhibition of the transcription factor E2A is required for the feedback inhibition of the pre-BCR signaling proteins.
authors: Department of Molecular Biology, Umeå University, SE-901 87 Umeå, Sweden.
authors: Jannek
authors: J
authors: Hauser
authors: Jiyoti
authors: J
authors: Verma-Gaur
authors: Thomas
authors: T
authors: Grundström
mesh_terms: D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D002118:Calcium / Q000276:immunology / Q000378:metabolism; D002147:Calmodulin / Q000276:immunology / Q000378:metabolism; D015536:Down-Regulation / Q000276:immunology; D054444:Immunoglobulin Light Chains, Surrogate / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D054420:Pre-B Cell Receptors / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: D018941:Antigens, CD19; D051792:Basic Helix-Loop-Helix Proteins; D002118:Calcium; D002147:Calmodulin; D054444:Immunoglobulin Light Chains, Surrogate; D054420:Pre-B Cell Receptors; C075668:Tcf3 protein, mouse