Faculty Collaboration Database

Spi-1 and Spi-B control the expression of the Grap2 gene in B cells. Gene 2005 Jun 20;353(1):134-46

Date

06/07/2005

Pubmed ID

15936902

DOI

10.1016/j.gene.2005.04.009

Scopus ID

2-s2.0-20444366129 (requires institutional sign-in at Scopus site)   18 Citations

Abstract

The Ets family members Spi-1 and Spi-B have been implicated in the regulation of genes important for B cell antigen receptor (BCR) signaling. Mice deficient in Spi-B exhibit reduced B cell proliferation in response to BCR cross-linking and impaired T cell-dependent immune responses. This defect is exacerbated in the presence of Spi-1 haplo-insufficiency (Spi1+/- SpiB-/-). Tyrosine phosphorylation and calcium mobilization induced by BCR engagement is diminished in Spi1+/- SpiB-/- B lymphocytes, although many key BCR signaling proteins are expressed, suggesting that Spi-1 and Spi-B regulate expression of additional, unidentified signaling molecules. We now demonstrate that expression of the adaptor protein Grap2 is impaired in Spi1+/- SpiB+/- and Spi1+/- SpiB-/- B lymphocytes. Analysis of two alternate murine Grap2 promoters revealed a functionally important Spi-1 and Spi-B DNA binding element located in the downstream promoter. Ectopic expression of Grap2 in Grap2-deficient B cells reduced the recruitment of BLNK to Igalpha and the phosphorylation of specific substrates. Regulation of BLNK recruitment was dependent upon the Grap2 proline-rich domain, while modulation of phosphorylation was dependent upon both the proline-rich and SH2 domains. These data indicate that Spi-1 and Spi-B directly regulate the expression of Grap2 and that Grap2 functions to modulate BCR signaling, but that reduced Grap2 expression is unlikely to account for the BCR signaling defects observed in Spi1+/- SpiB-/- B cells.

Author List

Garrett-Sinha LA, Hou P, Wang D, Grabiner B, Araujo E, Rao S, Yun TJ, Clark EA, Simon MC, Clark MR

Author

Sridhar Rao MD, PhD Associate Professor in the Pediatrics department at Medical College of Wisconsin

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

Adaptor Proteins, Signal Transducing
Animals
B-Lymphocytes
Base Sequence
Binding Sites
Blotting, Northern
Blotting, Western
Cell Line, Tumor
DNA-Binding Proteins
Down-Regulation
Electrophoretic Mobility Shift Assay
Gene Expression
Genotype
Heterozygote
Mice
Mice, Knockout
Molecular Sequence Data
Mutation
Oligonucleotides
Promoter Regions, Genetic
Protein Binding
Proto-Oncogene Proteins
RNA, Messenger
Receptors, Antigen, B-Cell
Sequence Alignment
Sequence Homology, Nucleic Acid
Signal Transduction
Spleen
Trans-Activators
Transcription Factors