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© The Rockefeller University Press, 0022-1007/1998/10/1297/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 7, October 5, 1998 1297-1306

Articles

Different Protein Tyrosine Kinases Are Required for B Cell Antigen Receptor–mediated Activation of Extracellular Signal–Regulated kinase, c-Jun NH2-terminal Kinase 1, and p38 Mitogen-activated Protein Kinase

Aimin Jiang*, Andrew Craxton{ddagger}, Tomohiro Kurosaki§, and Edward A. Clark*,{ddagger}

From the * Department of Microbiology and the {ddagger} Department of Immunology, University of Washington, Seattle, Washington 98195; and the § Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570, Japan

B cell antigen receptor (BCR) cross-linking activates three distinct families of nonreceptor protein tyrosine kinases (PTKs): src-family kinases, Syk, and Btk; these PTKs are responsible for initiating downstream events. BCR cross-linking in the chicken DT40 B cell line also activates three distinct mitogen-activated protein kinases (MAPKs): extracellular signal–regulated kinase (ERK)2, c-jun NH2-terminal kinase (JNK)1, and p38 MAPK. To dissect the functional roles of these PTKs in MAPK signaling, activation of MAPKs was examined in various PTK-deficient DT40 cells. BCR-mediated activation of ERK2, although maintained in Lyn-deficient cells, was abolished in Syk-deficient cells and partially inhibited in Btk-deficient cells, indicating that BCR-mediated ERK2 activation requires Syk and that sustained ERK2 activation requires Btk. BCR-mediated JNK1 activation was maintained in Lyn-deficient cells but abolished in both Syk- and Btk-deficient cells, suggesting that JNK1 is activated via a Syk- and Btk-dependent pathway. Consistent with this, BCR-mediated JNK1 activation was dependent on intracellular calcium and phorbol myristate acetate–sensitive protein kinase Cs. In contrast, BCR-mediated p38 MAPK activation was detected in all three PTK-deficient cells, suggesting that no single PTK is essential. However, BCR-mediated p38 MAPK activation was abolished in Lyn/Syk double deficient cells, demonstrating that either Lyn or Syk alone may be sufficient to activate p38 MAPK. Our data show that BCR-mediated MAPK activation is regulated at the level of the PTKs.

Key Words: B cell antigen receptor • mitogen-activated protein kinase • Lyn • Syk • Btk

Address correspondence to Edward A. Clark, Department of Microbiology, Box 357242, University of Washington, Seattle, WA 98195. Phone: 206-543-8706; Fax: 206-685-0305; E-mail: eclark{at}bart.rprc.washington.edu

Abbreviations used: ATF, activating transcription factor; BAPTA-AM, the acetoxymethyl ester of bis-(o-aminophenoxy) ethane-N,N,N', N'-tetraacetic acid; BCR, B cell antigen receptor; [Ca2+]i, intracellular cytoplasmic free Ca2+ concentration; ERK, extracellular signal-regulated kinase; GST, glutathione S-transferase; JNK, c-jun NH2-terminal kinase; MAPK, mitogen-activated protein kinase; MBP, myelin basic protein; PKC, protein kinase C; PLC-{gamma}2, phospholipase C-{gamma}2; PTK, protein tyrosine kinase.


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