The Journal of Experimental Medicine
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Published online 18 September 2000.
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© The Rockefeller University Press, 0022-1007/2000/9/847/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 6, September 18, 2000 847-856

Original Article

Involvement of Lat, Gads, and Grb2 in Compartmentation of Slp-76 to the Plasma Membrane

Masamichi Ishiaia, Mari Kurosakia, Kazunori Inabea, Andrew C. Chanb, Kazuo Sugamurac, and Tomohiro Kurosakia

a Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, Moriguchi 570-8506, Japan
b Center for Immunology, Division of Rheumatology, the Department of Medicine and the Department of Pathology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, Missouri 63110
c Department of Microbiology and Immunology, Tohoku University School of Medicine, Aoba-ku, Sendai 980-8575, Japan
Department of Molecular Genetics, Institute for Liver Research, Kansai Medical University, 10-15 Fumizono-cho, Moriguchi 570-8506, Japan.81-6-6994-609981-6-6993-9445

B cell linker protein (BLNK) and Src homology 2 domain–containing leukocyte protein of 76 kD (SLP-76) are adaptor proteins required for B cell receptor (BCR) and T cell receptor function, respectively. Here, we show that expression of SLP-76 cannot reconstitute BCR function in Zap-70+BLNK– B cells. This could be attributable to inability of SLP-76 to be recruited into glycolipid-enriched microdomains (GEMs) after antigen receptor cross-linking. Supporting this idea, the BCR function was restored when a membrane-associated SLP-76 chimera was enforcedly localized to GEMs. Moreover, we demonstrate that addition of both linker for activation of T cells (LAT) and Grb2-related adaptor downstream of Shc (Gads) to SLP-76 allow SLP-76 to be recruited into GEMs, whereby the BCR function is reconstituted. The Gads function was able to be replaced by overexpression of Grb2. In contrast to SLP-76, BLNK did not require Grb2 families for its recruitment to GEMs. Hence, these data suggest a functional overlap between BLNK and SLP-76, while emphasizing the difference in requirement for additional adaptor molecules in their targeting to GEMs.

Key Words: glycolipid-enriched microdomain • antigen receptor signaling • adaptor molecule • translocation • lymphocyte

Abbreviations used in this paper: BCR, B cell receptor; BLNK, B cell linker protein; [Ca2+]i, intracellular Ca2+ concentration; Gads, Grb2-related adaptor downstream of Shc; GEM, glycolipid-enriched microdomain; HA, hemagglutinin; IP3, inositol 1,4,5-trisphosphate; JNK, c-Jun NH2-terminal kinase; LAT, linker for activation of T cells; PLC, phospholipase C; PTK, protein tyrosine kinase; SH, Src homology; SLP-76, Src homology 2 domain–containing leukocyte protein of 76 kD.

© 2000 The Rockefeller University Press


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