B cell adaptor containing Src homology 2 domain (BASH) links B cell receptor signaling to the activation of hematopoietic progenitor kinase 1

被引:54
作者
Tsuji, S
Okamoto, M
Yamada, K
Okamoto, N
Goitsuka, R
Arnold, R
Kiefer, F
Kitamura, D
机构
[1] Sci Univ Tokyo, Res Inst Biol Sci, Div Mol Biol, Chiba 2780022, Japan
[2] Japan Sci & Technol Corp, Inheritance & Variat Grp, PRESTO, Chiba 2780022, Japan
[3] Max Planck Inst Physiol & Clin Res, WG Kerckoff Inst, D-61231 Bad Nauheim, Germany
关键词
antigen receptor signaling; BCR; BLNK; SH2; domain; I kappa B kinase;
D O I
10.1084/jem.194.4.529
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The B cell adaptor containing src homology 2 domain (BASH; also termed BLNK or SLP-65), is crucial for B cell antigen receptor (BCR)-mediated activation, proliferation, and differentiation of B cells. BCR-mediated tyrosine-phosphorylation of BASH creates binding sites for signaling effectors such as phospholipase C gamma (PLC gamma )2 and Vav, while the function of its COOH-terminal src homology 2 domain is unknown. We have now identified hematopoietic progenitor kinase (HPK)1, a STE20-related serine/threonine kinase, as a protein that inducibly interacts with the BASH SH2 domain. BCR, ligation induced rapid tyrosine-phosphorylation of HPK1 mainly by Syk and Lyn, resulting in its association with BASH and catalytic activation. BCR-mediated activation of HPK1 was impaired in Syk- or BASH-deficient B cells. The functional SH2 domain of BASH and Tyr-379 within HPK1 which we identified as a Syk-phosphorylation site were both necessary for interaction of both proteins and efficient HPK1 activation after BCR stimulation. Furthermore, HPK1 augmented, whereas its kinase-dead mutant inhibited I kappaB kinase beta (IKK beta) activation by BCR, engagement. These results reveal a novel BCR signaling path-way leading to the activation of HPK1 and subsequently IKK beta, in which BASH recruits tyrosine-phosphorylated HPK1 into the BCR signaling complex.
引用
收藏
页码:529 / 539
页数:11
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