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Molecular and Cellular Biology, November 1999, p. 7388-7398, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Functional Independence and Interdependence of the Src Homology Domains of Phospholipase C-gamma 1 in B-Cell Receptor Signal Transduction

Karen E. DeBell,1 Bogdan A. Stoica,1,dagger Maria-Concetta Verí,1 Angela Di Baldassarre,2 Sebastiano Miscia,2 Laurie J. Graham,1 Barbara L. Rellahan,1 Masamichi Ishiai,3 Tomohiro Kurosaki,3 and Ezio Bonvini1,*

Laboratory of Immunobiology, Division of Monoclonal Antibodies, Center for Biologics Evaluation and Research, Bethesda, Maryland 208921; Istituto di Morfologia Umana Normale, Università degli Studi "G. D'Annunzio," 66013 Chieti, Italy2; and Department of Molecular Genetics, Kansai Medical University, Moriguchi 570-8506, Japan3

Received 12 March 1999/Returned for modification 3 May 1999/Accepted 23 July 1999

B-cell receptor (BCR)-induced activation of phospholipase C-gamma 1 (PLCgamma 1) and PLCgamma 2 is crucial for B-cell function. While several signaling molecules have been implicated in PLCgamma activation, the mechanism coupling PLCgamma to the BCR remains undefined. The role of PLCgamma 1 SH2 and SH3 domains at different steps of BCR-induced PLCgamma 1 activation was examined by reconstitution in a PLCgamma -negative B-cell line. PLCgamma 1 membrane translocation required a functional SH2 N-terminal [SH2(N)] domain, was decreased by mutation of the SH3 domain, but was unaffected by mutation of the SH2(C) domain. Tyrosine phosphorylation did not require the SH2(C) or SH3 domains but depended exclusively on a functional SH2(N) domain, which mediated the association of PLCgamma 1 with the adapter protein, BLNK. Forcing PLCgamma 1 to the membrane via a myristoylation signal did not bypass the SH2(N) domain requirement for phosphorylation, indicating that the phosphorylation mediated by this domain is not due to membrane anchoring alone. Mutation of the SH2(N) or the SH2(C) domain abrogated BCR-stimulated phosphoinositide hydrolysis and signaling events, while mutation of the SH3 domain partially decreased signaling. PLCgamma 1 SH domains, therefore, have interrelated but distinct roles in BCR-induced PLCgamma 1 activation.

* Corresponding author. Mailing address: CBER, 29B/3NN10, 8800 Rockville Pike, Bethesda, MD 20892. Phone: (301) 827-0714. Fax: (301) 827-0852. E-mail: bonvini{at}box-b.nih.gov.

dagger Present address: Department of Biochemistry and Molecular Biology, Georgetown University, Washington, DC 20057.

Molecular and Cellular Biology, November 1999, p. 7388-7398, Vol. 19, No. 11
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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