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J. Biol. Chem., Vol. 282, Issue 37, 27181-27191, September 14, 2007

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Leupaxin Negatively Regulates B Cell Receptor Signaling^*

From the Laboratory of Immune Regulation, Biomedical Sciences Institutes, Agency for Science, Technology and Research and Singapore Immunology Network, Singapore 138673, Singapore

The role of the paxillin superfamily of adaptor proteins in B cell antigen receptor (BCR) signaling has not been studied previously. We show here that leupaxin (LPXN), a member of this family, was tyrosine-phosphorylated and recruited to the plasma membrane of human BJAB lymphoma cells upon BCR stimulation and that it interacted with Lyn (a critical Src family tyrosine kinase in BCR signaling) in a BCR-induced manner. LPXN contains four leucine-rich sequences termed LD motifs, and serial truncation and specific domain deletion of LPXN indicated that its LD3 domain is involved in the binding of Lyn. Of a total of 11 tyrosine sites in LPXN, we mutated Tyr²², Tyr⁷², Tyr¹⁹⁸, and Tyr²⁵⁷ to phenylalanine and demonstrated that LPXN was phosphorylated by Lyn only at Tyr⁷² and that this tyrosine site is proximal to the LD3 domain. The overexpression of LPXN in mouse A20 B lymphoma cells led to the suppression of BCR-induced activation of JNK, p38 MAPK, and, to a lesser extent, Akt, but not ERK and NFB, suggesting that LPXN can selectively repress BCR signaling. We further show that LPXN suppressed the secretion of interleukin-2 by BCR-activated A20 B cells and that this inhibition was abrogated in the Y72F LPXN mutant, indicating that the phosphorylation of Tyr⁷² is critical for the biological function of LPXN. Thus, LPXN plays an inhibitory role in BCR signaling and B cell function.

Received for publication, June 5, 2007 , and in revised form, July 16, 2007.

^* This work was supported by grants from the Biomedical Research Council of the Agency for Science, Technology and Research, Singapore. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Singapore Immunology Network, Lab 6-15, 61 Biopolis Dr., Proteos, Singapore 138673, Singapore. Tel.: 65-6586-9649; Fax: 65-6478-9477; E-mail: lam_kong_peng{at}immunol.a-star.edu.sg.

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