Signal-Transducing Adaptor Protein-2 Regulates Stromal Cell-Derived Factor-1α-Induced Chemotaxis in T Cells

Abstract

Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains pleckstrin and Src homology 2-like domains, as well as a YXXQ motif in its C-terminal region. Our previous studies revealed that STAP-2 regulates integrin-mediated T cell adhesion. In the present study, we find that STAP-2 expression affects Jurkat T cell migration after stromal cell-derived factor-1α (SDF-1α)-treatment. Furthermore, STAP-2-deficient T cells exhibit reduced cell migration after SDF-1α-treatment. Importantly, overexpression of STAP-2 in Jurkat T cells induces activation of small guanine triphosphatases, such as Rac1 and Cdc42. Regarding the mechanism for this effect, we found that STAP-2 associates with Vav1, the guanine-nucleotide exchanging factor for Rac1, and enhances downstream Vav1/Rac1 signaling. These results reveal a novel STAP-2-mediated mechanism for the regulation of SDF-1α-induced chemotaxis of T cells via activation of Vav1/Rac1 signaling.

STAP-2 interacts with and modulates BCR-ABL-mediated tumorigenesis

“…Thus, our data suggest a strong involvement of STAP-2 in the linkage of BCR-ABL and CXCR4. Coupled with our previous results indicating that STAP-2 enhances SDF-1a signaling through interactions with Vav (Sekine et al, 2009a), STAP-2 is likely to regulate SDF-1a/CXCR4 at multiple levels in CML cells. Therefore, STAP-2 is likely to play a crucial role in the pathogenesis of CML.…”

“…In this study we demonstrated that STAP-2 interacts with and modifies the function of various signaling or transcription molecules Yamamoto et al, 2003;Sekine et al, 2005Sekine et al, , 2006Sekine et al, , 2007bSekine et al, , 2009a. We also demonstrated that BCR-ABL acts as a novel binding partner for STAP-2 in the presence of both the STAP-2 SH2-like domain and STAP-2 Tyr250 phosphorylation.…”

“…We previously showed that STAP-2 regulates SDF-1a-induced T-cell migration via activation of Vav1/Rac1 signaling, suggesting that STAP-2 may be involved in chemokine functions (Sekine et al, 2009a). To clarify the tumor progression between BCR-ABL/STAP-2 and BCR-ABL-expressing Ba/F3 cells, we examined the mRNA expression levels of a series of chemokine receptors in the Ba/F3 transfectants.…”

“…Previous works in this laboratory found that STAP-2 have the ability to associate with and influence a variety of signaling or transcriptional molecules Yamamoto et al, 2003;Sekine et al, 2005Sekine et al, , 2006Sekine et al, , 2007bSekine et al, , 2009a, including the finding that STAP-2 can modulate the transcriptional activity of STAT3 and STAT5 Sekine et al, 2005), in addition to the FceRI and Toll-like receptor-mediated signals Sekine et al, 2006). Furthermore, thymocytes and peripheral T cells from STAP-2-deficient mice show enhanced interleukin-2 (IL-2)-or T cell receptor-dependent cell growth, integrin-mediated T-cell adhesion and impaired stromal cell-derived factor-1a (SDF-1a)-induced T-cell migration (Sekine et al, , 2007b(Sekine et al, , 2009a. Because STAP-2 is expressed in a variety of tissues and cells, such as lymphocytes, macrophages and hepatocytes, STAP-2 is also likely to function in a variety of different cells.…”

Signal-Transducing Adaptor Protein-2 Controls the IgE-Mediated, Mast Cell–Mediated Anaphylactic Responses

“…STAP-2 is expressed in a variety of tissues and cells, such as lymphocytes, macrophages, and hepatocytes (9), and its abundant expression pattern suggests that STAP-2 influences a variety of signaling or transcriptional molecules. Indeed, we previously reported that STAP-2 can modulate the transcriptional activity of STAT3 and STAT5, as well as TLR-mediated signals in macrophages and integrin-or SDF1a-mediated signals in T cells (9,(11)(12)(13)(14). Through these interactions, STAP-2 plays physiological roles in immune responses.…”