|Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2002: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2001: ¥1,800,000 (Direct Cost: ¥1,800,000)
Bruton's tyrosine kinase (Btk) plays pivotal roles in signal transduction pathways regulating survival, activation, proliferation, and differentiation of B-lineage lymphoid cells. Following ligation of B cell antigen receptors, Btk activation by the concerted actions of the PTKs, Lyn and Syk induces phospholipase C-2-mediated calcium mobilization. Mutations in the PH domain of human or mouse Btk cause maturational blocks at early stages of B cell ontogeny leading to XLA, or defective B cell development and function leading to xid mice, respectively. In order for fine dissection how PH domain involved in Btk-derived signaling pathways, we isolated BAM 11 (Btk-Associated Molecule# 11), which binds to the PH domain of Btk. Human homologue of mouse BAM11 is LTG19/ENL, one of the fusion partners involved in chromosomal translocations of 11q23, MLL/ALL- 1/HRX, in leukemia cells. Forced expression of a truncated form of BAM inhibited IL-5- or -BCR-mediated downstream signals.
In this study, we demonstrated that BAM11 has transcriptional activity, and that Btk upregulate transcriptional activity of BAM11 by interactions between BAM11 and Btk. Kinase activity of Btk is essential for the upregulate transcriptional activity of BAM11. Region on BAM11 necessary for transcriptional activation is on C-terminus and is different from the site that binds to Btk. TFII-I does not affect the transcriptional activity of BAM11. Co-immunoprecipitation experiments revealed that BAM11 associates with INI1/hSNF5, which is a component of SWI/SNF complex. These results suggest that BAM might be a key molecule transmitting signals as nucleocytoplasmic shuttle.