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Original Article

^a Division of Molecular Biology, Research Institute for Biological Sciences, Science University of Tokyo, Chiba 278-0022, Japan
^b Inheritance and Variation Group, PRESTO, Japan Science and Technology Corporation, Chiba 278-0022, Japan
^c Max-Planck-Institute for Physiological and Clinical Research, W.G. Kerckhoff-Institute, D-61231 Bad Nauheim, Germany
Research Institute for Biological Sciences, Science University of Tokyo, Yamazaki 2669, Noda, Chiba 278-0022, Japan.81-471-24-156181-471-23-9849

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 IB kinase β (IKKβ) activation by BCR engagement. These results reveal a novel BCR signaling pathway leading to the activation of HPK1 and subsequently IKKβ, in which BASH recruits tyrosine-phosphorylated HPK1 into the BCR signaling complex.

Key Words: antigen receptor signaling • BCR • BLNK • SH2 domain • IB kinase

Abbreviations used in this paper: BASH, B cell adaptor containing SH2 domain; BCR, B cell antigen receptor; CBP, calmodulin-binding protein; ERK, extracellular signal–regulated kinase; HPK, hematopoietic progenitor kinase; IKKβ, IB kinase β; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; NF, nuclear factor; PLC, phospholipase C; PTK, protein tyrosine kinase; WT, wild-type.

© 2001 The Rockefeller University Press

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