The Density of CD10 Corresponds to Commitment and Progression in the Human B Lymphoid Lineage

Requirements for human B lymphopoiesis are still poorly understood, and that has hampered investigation of differentiation events. For example, there are few cell surface antigens that can be used as milestones of lineage progression. The CD10 ectoenzyme is one such marker and has been used to define CLP, but we found substantial tissue specific variations in CD10 levels, and there was no information about how that corresponded to differentiation options.The aim of the present study was to use recently developed culture methods to assess the nature and differentiation potential of progenitors sorted according to CD10 density from umbilical cord blood (CB), adult bone marrow (BM) or G-CSF mobilized peripheral blood (PB). Many CD34(+) cells in BM express high levels of CD10, while low or low/negative CD10 densities were found on CD34(+) cells in CB or G-CSF mobilized PB, respectively. The relative abundance of CD10(Lo) versus CD10(Hi) cells only accounts for some CB versus BM differences. Almost all of the CD34(+) CD10(Hi) cells expressed CD19 and lymphocyte transcription factors and corresponded to loss of myeloid potential. A high degree of immunoglobulin D(H)-J(H) gene rearrangements was characteristic only of the CD10(Hi) subset. In contrast, the CD34(+) CD10(Lo) progenitors efficiently produced plasmacytoid and conventional dendritic cells as well as myeloid cells. These findings suggest a positive correlation between CD10 density and degree of differentiation. Although freshly isolated CD34(+) CD10(Hi) cells were in cycle, those from CB or BM expanded poorly in culture, suggesting regulators of populations remain to be discovered.Steps in human B lymphopoiesis have not been sufficiently studied, and we now show that increased CD10 expression corresponds to differentiation potential and stage. CD34(+) CD10(Hi) progenitors are obviously in the B lineage but may have progressed beyond the point where they can be expanded in culture

Potential of targeting signal-transducing adaptor protein-2 in cancer therapeutic applications

Adaptor proteins play essential roles in various intracellular signaling pathways. Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that possesses pleckstrin homology (PH) and Src homology 2 (SH2) domains, as well as a YXXQ signal transducer and activator of transcription 3 (STAT3)-binding motif in its C-terminal region. STAP-2 is also a substrate of breast tumor kinase (BRK). STAP-2/BRK expression is deregulated in breast cancers and enhances STAT3-dependent cell proliferation. In prostate cancer cells, STAP-2 interacts with and stabilizes epidermal growth factor receptor (EGFR) after stimulation, resulting in the upregulation of EGFR signaling, which contributes to cancer-cell proliferation and tumor progression. Therefore, inhibition of the interaction between STAP-2 and BRK/EGFR may be a possible therapeutic strategy for these cancers. For this purpose, peptides that interfere with STAP-2/BRK/EGFR binding may have great potential. Indeed, the identified peptide inhibitor successfully suppressed the STAP-2/EGFR protein interaction, EGFR stabilization, and cancer-cell growth. Furthermore, the peptide inhibitor suppressed tumor formation in human prostate- and lung-cancer cell lines in a murine xenograft model. This review focuses on the inhibitory peptide as a promising candidate for the treatment of prostate and lung cancers

Potential therapeutic applications of targeting signal-transducing adaptor protein-2 in autoimmune diseases

Adaptor proteins are involved in various immune responses via the modulation of many signaling pathways. Signal-transducing adaptor protein-2 (STAP-2) is an adaptor protein that contains typical domains such as the pleckstrin homology (PH) domain, Src homology domain, and a proline-rich region from the N-terminal region. In T cells, STAP-2 positively regulates T cell receptor (TCR)-mediated signaling by associating with CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) and lymphocyte-specific protein tyrosine kinase (LCK). Therefore, a peptide that inhibits the interaction between STAP-2 and CD3ζ ITAMs is likely to suppress TCR-mediated T cell activation, as well as T cell-mediated diseases. As expected, the peptide successfully inhibited the STAP-2/CD3ζ ITAM interaction and suppressed TCR-mediated signaling, cell proliferation, and interleukin (IL)-2 production in human/murine T cells. Furthermore, this inhibitor suppressed the pathogenesis of experimental autoimmune encephalomyelitis (EAE), which is widely recognized as a mouse model of multiple sclerosis, via the downregulation of T cell activation and infiltration of T helper (Th) 1/Th17 cells. These results suggest a new strategy for the treatment of multiple sclerosis and other immune diseases

Signal-transducing adaptor protein-2 modulates T-cell functions

Immune responses are orchestrated by controlling the initiation, magnitude, and duration of various signaling pathways. Adaptor proteins act as positive or negative regulators by targeting critical molecules of signaling cascades. Signal-transducing adaptor protein-2 (STAP-2) contains typical features of adaptor proteins, like a pleckstrin homology (PH) domain in the N-terminal region and a Src homology 2 (SH2) domain in the central region. STAP-2 binds to a variety of signaling or transcriptional molecules to control multiple steps of inflammatory/immune responses. STAP-2 enhances T-cell receptor (TCR)-mediated signaling via the association with TCR-proximal CD3ζ immunoreceptor tyrosine-based activation motifs (ITAMs) and lymphocyte-specific protein tyrosine kinase (Lck). STAP-2 decreases adherence of T-cells to fibronectin (FN) through an association with focal adhesion kinase (Fak) and Casitas B-lineage Lymphoma (c-Cbl), and increases chemotaxis of T-cells toward stromal cell-derived factor-1α (SDF-1α) through interactions with Vav1 and Ras-related C3 botulinum toxin substrate 1 (Rac1). STAP-2 positively regulates activation-induced cell deathrough the association with Fas and caspase-8. This review describes the current knowledge of the roles of STAP-2 in T-cell-dependent immune responses and the possible clinical utility of STAP-2-targeting therapies

The Satb1 Protein Directs Hematopoietic Stem Cell Differentiation toward Lymphoid Lineages

SummaryHow hematopoietic stem cells (HSCs) produce particular lineages is insufficiently understood. We searched for key factors that direct HSC to lymphopoiesis. Comparing gene expression profiles for HSCs and early lymphoid progenitors revealed that Satb1, a global chromatin regulator, was markedly induced with lymphoid lineage specification. HSCs from Satb1-deficient mice were defective in lymphopoietic activity in culture and failed to reconstitute T lymphopoiesis in wild-type recipients. Furthermore, Satb1 transduction of HSCs and embryonic stem cells robustly promoted their differentiation toward lymphocytes. Whereas genes that encode Ikaros, E2A, and Notch1 were unaffected, many genes involved in lineage decisions were regulated by Satb1. Satb1 expression was reduced in aged HSCs with compromised lymphopoietic potential, but forced Satb1 expression partly restored that potential. Thus, Satb1 governs the initiating process central to the replenishing of lymphoid lineages. Such activity in lymphoid cell generation may be of clinical importance and useful to overcome immunosenescence

STAP-2 Adaptor Protein Regulates Multiple Steps of Immune and Inflammatory Responses

Signal-transducing adaptor protein (STAP)-2 is an adaptor molecule involved in regulation of several intracellular signaling events in immune cells. STAP-2 contains a pleckstrin homology domain at the N-terminus, an src homology domain in the central portion and a proline-rich region at the C-terminus. STAP-2 also has a YXXQ motif, which is a potential signal transducer and activator of transcription (STAT)3-binding site. STAP-2 influences the STAT3 and STAT5 activity, integrin-mediated T cell adhesion, chemokine-induced T cell migration, Fas-mediated T cell apoptosis, Toll-like receptor-mediated macrophage functions, macrophage colony-stimulating factor-induced macrophage activation, and the high-affinity immunoglobulin E receptor-mediated mast cell activation. This article reviews the current understanding of roles of the STAP-2 during immune and/or inflammatory responses, and discusses possible therapeutic applications of targeting STAP-2 proteins in immune-related disorders

Possible Therapeutic Applications of Targeting STAP Proteins in Cancer

The signal-transducing adaptor protein (STAP) family, including STAP-1 and STAP-2, contributes to a variety of intracellular signaling pathways. The proteins in this family contain typical structures for adaptor proteins, such as Pleckstrin homology in the N-terminal regions and SRC homology 2 domains in the central regions. STAP proteins bind to inhibitor of kappaB kinase complex, breast tumor kinase, signal transducer and activator of transcription 3 (STAT3), and STAT5, during tumorigenesis and inflammatory/immune responses. STAP proteins positively or negatively regulate critical steps in intracellular signaling pathways through individually unique mechanisms. This article reviews the roles of the novel STAP family and the possible therapeutic applications of targeting STAP proteins in cancer

Current understanding of the role of tyrosine kinase 2 signaling in immune responses

Immune system is a complex network that clears pathogens, toxic substrates, and cancer cells. Distinguishing self-antigens from non-self-antigens is critical for the immune cell-mediated response against foreign antigens. The innate immune system elicits an early-phase response to various stimuli, whereas the adaptive immune response is tailored to previously encountered antigens. During immune responses, B cells differentiate into antibody-secreting cells, while naïve T cells differentiate into functionally specific effector cells [T helper 1 (Th1), Th2, Th17, and regulatory T cells]. However, enhanced or prolonged immune responses can result in autoimmune disorders, which are characterized by lymphocytemediated immune responses against self-antigens. Signal transduction of cytokines, which regulate the inflammatory cascades, is dependent on the members of the Janus family of protein kinases. Tyrosine kinase 2 (Tyk2) is associated with receptor subunits of immune-related cytokines, such as type I interferon, interleukin (IL)-6, IL-10, IL-12, and IL-23. Clinical studies on the therapeutic effects and the underlying mechanisms of Tyk2 inhibitors in autoimmune or chronic inflammatory diseases are currently ongoing. This review summarizes the findings of studies examining the role of Tyk2 in immune and/or inflammatory responses using Tyk2-deficient cells and mice