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Molecular and Cellular Biology, April 2002, p. 2524-2535, Vol. 22, No. 8
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.8.2524-2535.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

The Direct Recruitment of BLNK to Immunoglobulin {alpha} Couples the B-Cell Antigen Receptor to Distal Signaling Pathways

Shara Kabak,1,2 Brian J. Skaggs,2,3 Michael R. Gold,4 Michael Affolter,5 Kelly L. West,2 Mark S. Foster,2 Karyn Siemasko,2 Andrew C. Chan,6 Ruedi Aebersold,7 and Marcus R. Clark1,2*

Committees on Immunology,1 Cell Physiology,3 Section of Rheumatology, University of Chicago, Chicago, Illinois 60637,2 Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada,4 Nestec Ltd. Research Centre, Lausanne, Switzerland,5 Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110,6 Institute for Systems Biology, Seattle, Washington 981957

Received 6 November 2001/ Returned for modification 18 December 2001/ Accepted 24 December 2001

Following B-cell antigen receptor (BCR) ligation, the cytoplasmic domains of immunoglobulin {alpha} (Ig{alpha}) and Igß recruit Syk to initiate signaling cascades. The coupling of Syk to several distal substrates requires linker protein BLNK. However, the mechanism by which BLNK is recruited to the BCR is unknown. Using chimeric receptors with wild-type and mutant Ig{alpha} cytoplasmic tails we show that the non-immunoreceptor tyrosine-based activation motif (ITAM) tyrosines, Y176 and Y204, are required to activate BLNK-dependent pathways. Subsequent analysis demonstrated that BLNK bound directly to phospho-Y204 and that fusing BLNK to mutated Ig{alpha} reconstituted downstream signaling events. Moreover, ligation of the endogenous BCR induced Y204 phosphorylation and BLNK recruitment. These data demonstrate that the non-ITAM tyrosines of Ig{alpha} couple Syk activation to BLNK-dependent pathways.

* Corresponding author. Mailing address: University of Chicago, Department of Medicine, Section of Rheumatology, 5841 South Maryland Ave., MC-0930, Chicago, IL 60637. Phone: (773) 702-0202. Fax: (773) 702-8702. E-mail: mclark{at}medicine.bsd.uchicago.edu.

Molecular and Cellular Biology, April 2002, p. 2524-2535, Vol. 22, No. 8
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.8.2524-2535.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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