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.
Tsuji
S
S
Division of Molecular Biology, Research Institute for Biological Sciences, Science University of Tokyo, Chiba 278-0022, Japan.
Okamoto
M
M
Yamada
K
K
Okamoto
N
N
Goitsuka
R
R
Arnold
R
R
Kiefer
F
F
Kitamura
D
D
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D002352:Carrier Proteins / Q000502:physiology*; D002384:Catalysis; D004789:Enzyme Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D048868:Adaptor Proteins, Signal Transducing; C113939:B cell linker protein; D002352:Carrier Proteins; D010750:Phosphoproteins; D011947:Receptors, Antigen, B-Cell; D014443:Tyrosine; C102102:hematopoietic progenitor kinase 1; D017346:Protein Serine-Threonine Kinases