Modulation of TLR4 Signaling by a Novel Adaptor Protein Signal-Transducing Adaptor Protein-2 in Macrophages

Abstract

Signal transducing adaptor protein‐2 (STAP‐2) is a recently identified adaptor protein, that contains pleckstrin and Src homology 2 (SH2)‐like domains as well as a YXXQ motif in its C‐terminal region. Our previous studies have demonstrated that STAP‐2 binds to STAT3 and STAT5, and regulates their signaling pathways. In the present study, STAP‐2 was found to positively regulate LPS/TLR4‐mediated signals in macrophages. Disruption of STAP‐2 resulted in impaired LPS/TLR4‐induced cytokine production and NF‐κB activation. Conversely, overexpression of STAP‐2 enhanced these LPS/TLR4‐induced biological activities. STAP‐2, particularly its SH2‐like domain, bound to both MyD88 and IKK‐α/β, but not TRAF6 or IRAK1, and formed a functional complex composed of MyD88‐STAP‐2‐IKK‐α/β. These interactions augmented MyD88‐ and/or IKK‐α/β‐dependent signals, leading to enhancement of the NF‐κB activity. These results demonstrate that STAP‐2 may constitute an alternative LPS/TLR4 pathway for NF‐κB activation instead of the TRAF6‐IRAK1pathway.

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

“…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.…”

“…Its C-terminal region also has a proline-rich region and an YXXQ motif . 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.…”

The protein content of an adaptor protein, STAP-2 is controlled by E3 ubiquitin ligase Cbl

“…In this manuscript, we 4 have found that STAP-2 protein is degraded dependently of Casitas B-lineage Lymphoma (Cbl) protein. Cbl is composed of an N-terminal tyrosine-kinase-binding domain, ring-finger motif, a proline-rich region and a C-terminal ubiquitin-associated domain.…”

“…For example, STAP-2 interacts with STAT3 through its YXXQ motif [1] and with STAT5 through its PH and SH2-like domains [3], resulted in influencing their transcriptional activity. The SH2-like domain of STAP-2 binds to MyD88 and IKK-a/b, thereby modulating TLR4-mediated cytokine production and NFkB activation [4]. Both the SH2-like domain and the C-terminal proline-rich region of STAP-2 are required for the binding to PLC-g1, and the interaction leads to negative regulation of FceRI-mediated signals [5].…”

Interactions of STAP-2 with BRK and STAT3/5 in Breast Cancer Cells

“…As summarized in Table 1, STAP-2 interacts with, and modulates the function of, several signaling molecules including STAT3/5- Sekine et al, 2005), FcRI- , M-CSFR/c-FMS- and Toll-like receptor-mediated signals (Sekine et al, 2006). STAP-2 interacts with STAT3 through the C-terminal YXXQ motif and enhances STAT3 transcriptional activity.…”