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Blood, 15 October 2006, Vol. 108, No. 8, pp. 2703-2711.
Prepublished online as a Blood First Edition Paper on June 22, 2006; DOI 10.1182/blood-2006-05-024968.
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IMMUNOBIOLOGY
BASH-novel PKC-Raf-1 pathway of pre-BCR signaling induces  gene rearrangement
Mutsumi Yamamoto,
Katsuhiko Hayashi,
Takuya Nojima,
Yumi Matsuzaki,
Yohei Kawano,
Hajime Karasuyama,
Ryo Goitsuka, and
Daisuke Kitamura
From the Division of Molecular Biology, Research Institute for Biological Sciences, Tokyo University of Science, Chiba, Japan; Department of Physiology, Keio University School of Medicine, Tokyo, Japan; and Department of Immune Regulation, Tokyo Medical and Dental University Graduate School, Tokyo, Japan.
The pre-B-cell receptor (pre-BCR) is thought to signal transcriptional activation of the immunoglobulin light (L) chain gene locus, proceeding to its V-J rearrangement. The pre-BCR signaling pathway for this process is largely unknown but may involve the adaptor protein BASH (BLNK/SLP-65). Here we report that the pre-B leukemia cell lines established from affected BASH-deficient mice rearrange  L-chain gene locus and down-regulate pre-BCR upon PMA treatment or BASH reconstitution. Analyses with specific inhibitors revealed that activation of novel PKC (nPKC) and MEK, but not Ras, is necessary for the rearrangement. Accordingly, retroviral transduction of active PKC , PKC , or Raf-1, but not Ras, induced the gene rearrangement and expression in the pre-B-cell line. Tamoxifen-mediated BASH reconstitution resulted in the translocation of PKC to the plasma membrane and chain expression. These data make evident that the Ras-independent BASH-nPKC-Raf-1 pathway of pre-BCR signaling induces the L-chain gene rearrangement and expression.
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