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¹ Ontario Cancer Institute, University Health Network, and McLaughlin Center for Molecular Medicine, University of Toronto, Toronto, Ontario, M5G 2C1, Canada
² The Arthur and Sonia Labatt Brain Tumor Research Center, The Hospital for Sick Children, Toronto, Ontario M5G 1X8, Canada

Address correspondence to Jaime O. Claudio, McLaughlin Centre for Molecular Medicine, 620 University Ave., Suite 8-201D, Toronto, Ontario M5G 2C1, Canada. Phone: (416) 946-4501, ex. 4728; Fax: (416) 946-2087; email: jclaudio{at}uhnres.utoronto.ca

HACS1 is a Src homology 3 and sterile alpha motif domain–containing adaptor that is preferentially expressed in normal hematopoietic tissues and malignancies including myeloid leukemia, lymphoma, and myeloma. Microarray data showed HACS1 expression is up-regulated in activated human B cells treated with interleukin (IL)-4, CD40L, and anti–immunoglobulin (Ig)M and clustered with genes involved in signaling, including TNF receptor–associated protein 1, signaling lymphocytic activation molecule, IL-6, and DEC205. Immunoblot analysis demonstrated that HACS1 is up-regulated by IL-4, IL-13, anti-IgM, and anti-CD40 in human peripheral blood B cells. In murine spleen B cells, Hacs1 can also be up-regulated by lipopolysaccharide but not IL-13. Induction of Hacs1 by IL-4 is dependent on Stat6 signaling and can also be impaired by inhibitors of phosphatidylinositol 3-kinase, protein kinase C, and nuclear factor B. HACS1 associates with tyrosine-phosphorylated proteins after B cell activation and binds in vitro to the inhibitory molecule paired Ig-like receptor B. Overexpression of HACS1 in murine spleen B cells resulted in a down-regulation of the activation marker CD23 and enhancement of CD138 expression, IgM secretion, and Xbp-1 expression. Knock down of HACS1 in a human B lymphoma cell line by small interfering ribonucleic acid did not significantly change IL-4–stimulated B cell proliferation. Our study demonstrates that HACS1 is up-regulated by B cell activation signals and is a participant in B cell activation and differentiation.

Key Words: B lymphocytes • interleukin-4 • signaling • gene expression • adaptor protein

Abbreviations used in this paper: BCR, B cell receptor; Bis I, bisindolylmaleimide I; EST, expressed sequence tag; HL, Hodgkin lymphoma; ITIM, immunoreceptor tyrosine-based motif; MAPK, mitogen-activated protein kinase; PDTC, pyrrolidinedithiocarbamate; PI, phosphatidylinositol; PKC, protein kinase C; SAM, sterile alpha motif; siRNA, small interfering RNA; SH3, Src homology 3.

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This article has been cited by other articles:

• Herrin, B. R., Justement, L. B. (2006). Expression of the Adaptor Protein Hematopoietic Src Homology 2 is Up-Regulated in Response to Stimuli That Promote Survival and Differentiation of B Cells. J. Immunol. 176: 4163-4172 [Abstract] [Full Text]  

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