The SH3-SAM adaptor HACS1 is up-regulated in B cell activation signaling cascades.
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 kappaB. 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.
Zhu
Yuan Xiao
YX
Ontario Cancer Institute, University Health Network, McLaughlin Centre for Molecular Medicine, University of Toronto, Ontario M5G 2C1, Canada.
Benn
Sally
S
Li
Zhi Hua
ZH
Wei
Ellen
E
Masih-Khan
Esther
E
Trieu
Young
Y
Bali
Meenakshi
M
McGlade
C Jane
CJ
Claudio
Jaime O
JO
Stewart
A Keith
AK
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000502:physiology; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism*; D002454:Cell Differentiation; D005786:Gene Expression Regulation; D006801:Humans; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000502:physiology; D050800:STAT6 Transcription Factor; D015398:Signal Transduction / Q000502:physiology*; D015534:Trans-Activators / Q000502:physiology; D014443:Tyrosine / Q000378:metabolism; D015854:Up-Regulation
D033942:Adaptor Proteins, Vesicular Transport; D016328:NF-kappa B; C435526:SAMSN1 protein, human; C000596182:SLy2 protein, mouse; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human; C494100:Stat6 protein, mouse; D015534:Trans-Activators; D015847:Interleukin-4; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D011493:Protein Kinase C