Biomedical subjects

Erik J Peterson

Publications and source records attributed to Erik J Peterson.

6 recordsLinked to original sources

PubMed2006

ADAP is dispensable for NK cell development and function.

NK cells are key mediators of the innate immune response and anti-tumor surveillance. Adhesion and degranulation-promoting adapter protein (ADAP, formerly known as SLAP-130 or Fyb) is a hematopoietic-specific adapter that is required for efficient TCR signaling and T cell activation. Herein, we examine a potential role for ADAP in NK development and function. ADAP is expressed in primary NK cells and in IL-2 stimulated lymphokine-activated killers. However, ADAP-deficient mice show no defects in NK development. Further, ADAP is dispensable for key NK functions, including cytotoxicity in response to engagement of activating receptors, cytokine production, conjugate formation and tumor suppression in vivo. These results indicate that, unlike events stimulated by TCR engagement, signaling events engaged by immunoreceptor tyrosine-based activation motif-associated and cytokine receptors on NK cells can occur independently of ADAP.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Adhesion- and degranulation-promoting adapter protein is required for efficient thymocyte development and selection.

Adhesion- and degranulation-promoting adapter protein (ADAP) is required in TCR-induced activation and proliferation of peripheral T cells. Loss of ADAP also impairs TCR-initiated inside-out activation of the integrin LFA-1 (CD11a/CD18, alphaLbeta2). In this study, we demonstrate that ADAP-deficient CD4/CD8 double-positive (DP) cells have a diminished ability to proliferate, and that these DP thymocytes up-regulate CD69 poorly in vivo. Moreover, in both MHC class I- and class II-restricted TCR transgenic models, loss of ADAP interferes with both positive and negative selection. ADAP deficiency also impairs the ability of transgene-bearing DP thymocytes to form conjugates with Ag-loaded presenting cells. These findings suggest that ADAP is critical for thymocyte development and selection.

Adaptor Proteins, Signal Transducing↗

PubMed2006

Gene expression profiling in human autoimmunity.

Human autoimmune diseases are well suited for the application of gene expression profiling. Sampling of blood cells and target tissues has already revealed many important pathways contributing to this spectrum of disorders, and many commonalities are emerging. For instance, clinically distinct diseases such as systemic lupus erythematosus, Sjögren's syndrome, dermatomyositis, and psoriasis all show evidence for dysregulation of the type I interferon pathway. These data suggest that autoimmune diseases will eventually be categorized at the level of gene expression. This work has led to advances in our understanding of disease pathogenesis and in the future promises to facilitate assessments of disease activity and improve targeting of therapies. Here, we review the literature on gene profiling in human autoimmune diseases and provide perspective on the current state of the art.

Autoimmune Diseases↗

PubMed2004

Differential requirement for adapter proteins Src homology 2 domain-containing leukocyte phosphoprotein of 76 kDa and adhesion- and degranulation-promoting adapter protein in FcepsilonRI signaling and mast cell function.

The adapter molecule Src homology 2 (SH2) domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) is essential for FcepsilonRI-mediated signaling, degranulation and IL-6 production in mast cells. To test the structural requirements of SLP-76 in mast cell signaling and function, we have studied the functional responses of murine bone marrow-derived mast cells (BMMCs) expressing mutant forms of SLP-76. We found that the N-terminal tyrosines as well as the central proline-rich region of SLP-76 are required for participation of SLP-76 in FcepsilonRI-mediated signaling and function. The C-terminal SH2 domain of SLP-76 also contributes to optimal function of SLP-76 in mast cells. Another adapter molecule, adhesion- and degranulation-promoting adapter protein (ADAP), is known to bind the SH2 domain of SLP-76, and cell line studies have implicated ADAP in mast cell adhesion and FcepsilonRI-induced degranulation. Surprisingly, we found that mast cells lacking ADAP expression demonstrate no defects in FcepsilonRI-induced adhesion, granule release, or IL-6 production, and that ADAP-deficient mice produce a normal passive systemic anaphylactic response. Thus, failure to bind ADAP does not underlie the functional defects exhibited by SLP-76 SH2 domain mutant-expressing mast cells.

Adaptor Proteins, Signal Transducing↗

PubMed2004

PRAM-1 is required for optimal integrin-dependent neutrophil function.

PML-retinoic acid receptor alpha (RARalpha) regulated adaptor molecule 1 (PRAM-1) is an intracellular adaptor molecule that is upregulated during the induced granulocytic differentiation of promyelocytic leukemic cells and during normal human myelopoiesis. This report describes the generation of PRAM-1-deficient mice and an analysis of the function of this adaptor in neutrophil differentiation and mature neutrophil function. We demonstrate here that neutrophil differentiation is not impaired in PRAM-1-deficient mice and that PRAM-1-deficient neutrophils function normally following engagement of Fcgamma receptors. In contrast, mature PRAM-1-null neutrophils exhibit significant defects in adhesion-dependent reactive oxygen intermediate production and degranulation. Surprisingly, other integrin-dependent responses, such as cell spreading and activation of several signaling pathways, are normal. Together, these findings demonstrate the uncoupling of key integrin-dependent responses in the absence of PRAM-1 and show this adaptor to be critical for select integrin functions in neutrophils.

Adaptor Proteins, Signal Transducing↗

PubMed2003

The TCR ADAPts to integrin-mediated cell adhesion.

Adapter proteins regulate leukocyte signal transduction through recruitment of effector molecules to multiprotein complexes. Recent studies in Adhesion and Degranulation promoting Adapter Protein (ADAP)-deficient mice have established that the cytoplasmic phosphoprotein ADAP is required for optimal, mature T-cell proliferation. Furthermore, ADAP plays a key role in T-cell antigen receptor (TCR)-mediated 'inside out' signaling leading to integrin activation and to enhanced cellular adhesion to integrin ligands. ADAP associates physically with molecules known to play roles in the regulation of TCR-stimulated actin polymerization. These associations support the hypothesis that ADAP functions in actin cytoskeletal reorganization leading to cellular adhesion and activation.

Adaptor Proteins, Signal Transducing↗