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

J Exp Med. 2001 Aug 20;194(4):529-39. doi: 10.1084/jem.194.4.529.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

  • Adaptor Proteins, Signal Transducing
  • B cell linker protein
  • Carrier Proteins
  • Phosphoproteins
  • Receptors, Antigen, B-Cell
  • Tyrosine
  • hematopoietic progenitor kinase 1
  • Protein-Serine-Threonine Kinases