Enhanced adaptive immunity in mice lacking the immunoinhibitory adaptor Hacs1

Wang, Dingyan; Stewart, A. Keith; Zhuang, Lin; Zhu, Yuanxiao; Wang, Youdong; Shi, Chang‐Xin; Keating, Armand; Slutsky, Arthur S.; Zhang, Haibo; Wen, Xiao‐Yan

doi:10.1096/fj.09-140806

Cited by 26 publications

(48 citation statements)

References 31 publications

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“…SLY2 is expressed in normal and hematopoietic tissues and is upregulated in B cells stimulated with IL-4, IL-13, anti-IgM, and anti-CD40, suggesting a role in B cell activation and differentiation cascades (12). Moreover, Sly2 2/2 mice have increased Th1 and Th2 humoral immune responses, suggesting that Sly2 acts as an immunosuppressor (43). The results presented in this study suggest that SASH1 also functions in immune regulation, but in nonlymphoid cells, and, to our knowledge, describe for the first time a molecular function for SASH1 in innate immunity.…”

Section: Discussionmentioning

confidence: 99%

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

Dauphinee

Clayton

Hussainkhel

et al. 2013

The Journal of Immunology

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Recognition of microbial products by TLRs is critical for mediating innate immune responses to invading pathogens. In this study, we identify a novel scaffold protein in TLR4 signaling called SAM and SH3 domain containing protein 1 (SASH1). Sash1 is expressed across all microvascular beds and functions as a scaffold molecule to independently bind TRAF6, TAK1, IκB kinase α, and IκB kinase β. This interaction fosters ubiquitination of TRAF6 and TAK1 and promotes LPS-induced NF-κB, JNK, and p38 activation, culminating in increased production of proinflammatory cytokines and increased LPS-induced endothelial migration. Our findings suggest that SASH1 acts to assemble a signaling complex downstream of TLR4 to activate early endothelial responses to receptor activation.

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Section: Discussionmentioning

confidence: 99%

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

Dauphinee

Clayton

Hussainkhel

et al. 2013

The Journal of Immunology

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“…SAMSN1 is primarily expressed in human immune tissues as well as in cell lines and primary cells derived from patients with acute myeloid leukemia and multiple myeloma (15,37). In addition, SAMSN1 expression is upregulated by signaling factors that promote the activation and differentiation of B-cells (11,13).…”

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confidence: 99%

Prognostic relevance of SAMSN1 expression in gastric cancer

et al. 2016

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Abstract.The prognosis for patients with advanced gastric cancer (GC) remains poor. The identification of biomarkers relevant to the recurrence and metastasis of GC is advantageous for stratifying patients and proposing novel molecular targets. In the present study the oncological roles of SAM domain, SH3 domain and nuclear localization signals 1 (SAMSN1), a mediator of B-cell function, were elucidated in GC. The expression and methylation status of SAMSN1 were investigated in a panel of 11 GC cell lines. Immunohistochemical staining was performed to determine the pattern of SAMSN1 protein expression in gastric tissues. The prognostic impact of SAMSN1 expression was determined by analyzing 175 pairs of surgically resected gastric tissues. A marked decrease in the level of SAMSN1 mRNA was detected in 8/11 GC cell lines as compared with that in a non-transformed intestinal epithelium cell line (FHs 74) without promoter methylation. The mean expression level of SAMSN1 mRNA was reduced in GC tissues compared with normal adjacent tissues, an observation that was independent of tumor differentiation. The pattern of SAMSN1 protein expression was significantly correlated with that of SAMSN1 mRNA. Low SAMSN1 mRNA expression was significantly associated with tumor size (>60 mm; P=0.026) and shorter overall survival times (P=0.004). Multivariate analysis identified low SAMSN1 mRNA expression as an independent prognostic factor for poor overall survival (hazard ratio, 1.80; 95% confidence interval, 1.07-3.05; P= 0.025). The difference in survival between the low and high SAMSN1 expression groups was more marked in patients with stage II/III GC compared to those with stage IV GC. In patients with stage II/III GC who underwent curative surgery, low SAMSN1 expression was associated with reduced disease free survival times. The results of the present study indicate that downregulation of SAMSN1 transcription may affect the progression and recurrence of GC, and therefore may represent a novel biomarker of GC.

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“…The expression of the putative adapter protein SLy2 is physiologically up-regulated in the process of B cell activation (15), leading to increased differentiation and decreased proliferation (16), but the cellular consequences of increased SLy2 expression remain poorly understood.…”

Section: Generation and Characterization Of Sly2 Model Cell Lines-mentioning

confidence: 99%

“…Furthermore, overexpression of SLy2 in murine splenic B cells results in an inhibition of proliferation and in an enhancement of differentiation, suggesting a role for SLy2 in B cell differentiation to plasma cells (15). Recently, SLy2-deficient mice were generated (16). Although bone marrow B cell development and splenic B and T cell populations are normal, SLy2 Ϫ/Ϫ mice show enhanced adaptive immunity, and splenic B cells showed increased proliferation upon B cell receptor stimulation, demonstrating that SLy2 acts an antiproliferative immunoinhibitory adapter protein in vivo (16).…”

mentioning

confidence: 99%

“…Recently, SLy2-deficient mice were generated (16). Although bone marrow B cell development and splenic B and T cell populations are normal, SLy2 Ϫ/Ϫ mice show enhanced adaptive immunity, and splenic B cells showed increased proliferation upon B cell receptor stimulation, demonstrating that SLy2 acts an antiproliferative immunoinhibitory adapter protein in vivo (16). SLy2 Ϫ/Ϫ mice phenocopy certain aspects of paired Ig-like receptor B (PIR-B)-deficient mice, and yeast twohybrid screening and in vitro binding data suggested that PIR-B functions as a SLy2-interacting protein (15).…”

mentioning

confidence: 99%

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Immunoinhibitory Adapter Protein Src Homology Domain 3 Lymphocyte Protein 2 (SLy2) Regulates Actin Dynamics and B Cell Spreading

Holleben

Gohla

Janssen

et al. 2011

Journal of Biological Chemistry

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Appropriate B cell activation is essential for adaptive immunity. In contrast to the molecular mechanisms that regulate positive signaling in immune responses, the counterbalancing negative regulatory pathways remain insufficiently understood. The Src homology domain 3 (SH3)-containing adapter protein SH3 lymphocyte protein 2 (SLy2, also known as hematopoietic adapter-containing SH3 and sterile ␣-motif (SAM) domains 1; HACS1) is strongly up-regulated upon B cell activation and functions as an endogenous immunoinhibitor in vivo, but the underlying molecular mechanisms of SLy2 function have been elusive. We have generated transgenic mice overexpressing SLy2 in B and T cells and have studied the biological effects of elevated SLy2 levels in Jurkat and HeLa cells. Our results demonstrate that SLy2 induces Rac1-dependent membrane ruffle formation and regulates cell spreading and polarization and that the SLy2 SH3 domain is essential for these effects. Using immunoprecipitation and confocal microscopy, we provide evidence that the actin nucleation-promoting factor cortactin is an SH3 domain-directed interaction partner of SLy2. Consistent with an important role of SLy2 for actin cytoskeletal reorganization, we further show that SLy2-transgenic B cells are severely defective in cell spreading. Together, our findings extend our mechanistic understanding of the immunoinhibitory roles of SLy2 in vivo and suggest that the physiological up-regulation of SLy2 observed upon B cell activation functions to counteract excessive B cell spreading.During cell spreading, a dynamic cortical network of actin fibers is constructed that enables the leading edge to protrude (1). In the adaptive immune system, cortical actin remodeling is essential for the early spreading and contraction displayed by B cells in response to membrane-bound antigens, which maximizes the amount of antigen interacting with the cognate B cell receptor (2). Although the cytomechanical events that underlie B cell responses to antigen and the elaboration of an immunological synapse (IS) 3 appear to be related to cell attachment and spreading, the intracellular molecules that regulate these processes are still incompletely understood (3-5).Reorganization of the actin cytoskeleton in response to diverse adhesive or antigenic stimuli is dependent on adapter and scaffold proteins that physically integrate signaling inputs via their protein/protein interaction domains (6). The Src homology domain 3 (SH3), first described in the nonreceptor protein-tyrosine kinase Src (7, 8), mediates binding to prolinerich sequences in effector proteins. SH3 domains are the most abundant and best characterized protein/protein interaction domains in adapter proteins, although novel SH3 domain-containing proteins with unknown functions continue to be discovered (9).The SH3-domain protein expressed in the lymphocyte (SLy) family of proteins comprises three members SLy1, SLy2 (also known as hematopoietic adapter containing SH3 and SAM domains 1, HACS1), and the SAM and SH3 domain-containin...

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Enhanced adaptive immunity in mice lacking the immunoinhibitory adaptor Hacs1

Cited by 26 publications

References 31 publications

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

Prognostic relevance of SAMSN1 expression in gastric cancer

Immunoinhibitory Adapter Protein Src Homology Domain 3 Lymphocyte Protein 2 (SLy2) Regulates Actin Dynamics and B Cell Spreading

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