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Original Article |
Correspondence to: Daisuke Kitamura, Research Institute for Biological Sciences, Science University of Tokyo, Yamazaki 2669, Noda, Chiba 278-0022, Japan. Tel:81-471-23-9849 Fax:81-471-24-1561 E-mail:kitamura{at}rs.noda.sut.ac.jp.
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
(PLC)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
B kinase ß (IKKß) activation by BCR engagement. These results reveal a novel BCR signaling pathway leading to the activation of HPK1 and subsequently IKKß, in which BASH recruits tyrosine-phosphorylated HPK1 into the BCR signaling complex.
Key Words:
antigen receptor signaling, BCR, BLNK, SH2 domain, IB kinase
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