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

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

Pubmed ID: 11514608

Authors

  • Tsuji S
  • Okamoto M
  • Yamada K
  • Okamoto N
  • Goitsuka R
  • Arnold R
  • Kiefer F
  • Kitamura D

Journal

The Journal of experimental medicine

Publication Data

August 20, 2001

Associated Grants

None

Mesh Terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Carrier Proteins
  • Catalysis
  • Enzyme Activation
  • Mice
  • Mice, Inbred C57BL
  • Phosphoproteins
  • Phosphorylation
  • Protein-Serine-Threonine Kinases
  • Receptors, Antigen, B-Cell
  • Signal Transduction
  • Tyrosine
  • src Homology Domains