Ribp, a Novel Rlk/Txk- and Itk-Binding Adaptor Protein That Regulates T Cell Activation

Abstract

A novel T cell–specific adaptor protein, RIBP, was identified based on its ability to bind Rlk/Txk in a yeast two-hybrid screen of a mouse T cell lymphoma library. RIBP was also found to interact with a related member of the Tec family of tyrosine kinases, Itk. Expression of RIBP is restricted to T and natural killer cells and is upregulated substantially after T cell activation. RIBP-disrupted knockout mice displayed apparently normal T cell development. However, proliferation of RIBP-deficient T cells in response to T cell receptor (TCR)-mediated activation was significantly impaired. Furthermore, these activated T cells were defective in the production of interleukin (IL)-2 and interferon γ, but not IL-4. These data suggest that RIBP plays an important role in TCR-mediated signal transduction pathways and that its binding to Itk and Rlk/Txk may regulate T cell differentiation.

The C terminus of T cell‐specific adapter protein (TSAd) is necessary for TSAd‐mediated inhibition of Lck activity

“…Recently the adapter protein ALX or HSH2 was found to have substantial homology to TSAd [30]. Both ALX and TSAd were found to inhibit the activity of IL-2 promoter constructs [9,30]; however, TSAd has also been found to promote IL-2 promoter activity [10], and activated T cells from TSAd knockout mice express less IL-2 [6]. These apparently conflicting results [11] may be explained in several ways.…”

“…One possibility is that overexpression of a protein may lead to an imbalance between this protein and its different binding partners which participate in conferring its function [31]. Another likely possibility is that TSAd may have several functions in the cell, as TSAd has been cloned as the interaction partner of several other signaling molecules [4,[6][7][8]. The spontaneous systemic autoimmune disease and deficient apoptosis of activated T cells seen in TSAd knockout mice [11] could be associated with reduced expression of IL-2 [6,11].…”

“…The murine TSAd homologue Lad/RIBP, which displays 76% sequence homology with TSAd [6], may interact with the Lck SH2 domain [5]. To explore whether human TSAd may interact with Lck, TSAd was immunoprecipitated from Jurkat T cells or Jurkat T cells stably transfected with myc-tagged TSAd, and the immunoprecipitates were examined for the presence of Lck.…”

“…Others have shown that TSAd is translocated to the nucleus in activated Jurkat T cells, and proposed that TSAd could function as a transcription adapter protein positively influencing IL-2 promoter activity [10]. T cells from mice lacking TSAd expression show reduced production of IL-2 and IFN-c [6], and these mice develop a spontaneous systemic autoimmune disease as they grow older [11]. TSAd thus appears to have multiple and apparently opposing functions in the cell.…”

“…TSAd has been found to interact with the vascular endothelial growth factor receptor 2 (VEGFR-2) in endothelial cells [4]. The murine homologue of TSAd has been cloned as interaction partner for the tyrosine kinases Lck [5] and Itk [6], the mitogenactivated protein kinase kinase 2 (MEKK2) [7] and the adapter protein Grb2 [8]. We previously showed that TSAd inhibits proximal signaling events in Jurkat T cells stably expressing TSAd, possibly by interfering with Lck activity [9].…”