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Stimulation Through the T Cell Receptor Leads to Interactions Between SHB and Several Signaling Proteins

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Stimulation Through the T Cell Receptor Leads to Interactions Between SHB and Several Signaling Proteins Oncogene (1998) 16, 891 ± 901 1998 Stockton Press All rights reserved 0950 ± 9232/98 $12.00 Stimulation through the T cell receptor leads to interactions between SHB and several signaling proteins Michael Welsh1, Zhou Songyang5, J Daniel Frantz2,4, Thomas TruÈ b2,4, Kris A Reedquist3,4, TorbjoÈ rn Karlsson1, Masaya Miyazaki2,4, Lewis C Cantley5, Hamid Band3,4 and Steven E Shoelson2,4 1Department of Medical Cell Biology, Uppsala University, Uppsala, Sweden; 2Research Division, Joslin Diabetes Center, Boston, Massachusetts, USA; 3Lymphocyte Biology Section, Division of Rheumatology and Immunology, and 4Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA; 5Division of Signal Transduction, Beth Israel Hospital, Harvard Medical School, Boston, Massachusetts, USA Shb is a recently described Src homology 2 (SH2) the TCR associated CD3 and z chains (Weiss and domain-containing adaptor protein. Here we show that Littman, 1994). The ITAMs are repeated sequences of Shb is expressed in lymphoid tissues, and is recruited YXXL separated by 6 ± 8 amino acids and their into signaling complexes upon activation of Jurkat T tyrosine phosphorylation generates binding sites for cells. Grb2 binds proline-rich motifs in Shb via its SH3 Src homology 2 (SH2) domains of signaling molecules, domains. As a result, a number of proteins detected in such as those of ZAP 70 (Chan et al., 1992; Hutchcroft anti-Shb and anti-Grb2 immunoprecipitates are shared, et al., 1992). This initiates a cascade of reactions including phosphoproteins of 22, 36/38, 55/57 and involving the adaptor protein p36/38 (Weber et al., 70 kDa. Shb-association with p22, which represents the 1992; Gilliland et al., 1992; Sieh et al., 1994), Lnk T cell receptor associated z chain, occurs through the (Huang et al., 1995), Grb2 (Ravichandran et al., 1993) Shb SH2 domain. The central region of Shb binds p36/ and the signaling pathways of phospholipase C g, PI-3 38. Since this interaction was inhibited by phosphotyr- kinase and MAP kinase (Ravichandran et al., 1993; osine, this region of Shb is likely to contain a non-SH2 Secrist et al., 1991; Thompson et al., 1992). Eventually, PTB (phosphotyrosine binding) domain. The Shb PTB a signal is propagated which induces altered gene domain was found to preferentially bind the sequence transcription, IL-2 production, dierentiation and a Asp-Asp-X-pTyr when incubated with a phosphopeptide modi®cation of the balance between cell proliferation library. A peptide corresponding to a phosphorylation and apoptosis (Weiss and Littman, 1994; Perlmutter et site in 34 kDa Lnk inhibited association between Shb al., 1993). and p36/38. Overexpression of Shb in Jurkat cells led to Shb is a recently characterized adaptor protein increased basal phosphorylation of Shb-associated p36/ (Welsh et al., 1994), with an SH2 domain in its C- 38 and p70 proteins. Inactivation of the Shb SH2 domain terminus and proline-rich sequences in its N-terminus. by an R522K mutation resulted in a reduced stimulation The cDNA sequence contains two potential translation of tyrosine phosphorylation of several proteins in initiation sites, the ®rst corresponding to a protein response to CD3 crosslinking when expressed in Jurkat product migrating as 66 kDa and containing ®ve cells. Together, our results show three distinct domains proline-rich motifs (Welsh et al., 1994; Karlsson and of Shb all participate in the formulation of multimeric Welsh, 1996) and the second to a product migrating as signaling complexes in activated T cells. These results 55 kDa and containing two proline-rich motifs. The indicate that the Shb protein functions in T cell receptor proline-rich sequences of Shb have been shown to signaling. interact with the Src homology 3 (SH3) domains of the p85 subunit of PI-3 kinase, Src tyrosine kinase and the Keywords: Shb; Jurkat T cells; T cell receptor; p36/38; epidermal growth factor-associated adaptor protein SH2 domain; PTB domain Eps8 (Karlsson et al., 1995). The SH2 domain of Shb binds the autophosphorylated PDGF b-receptor and the FGF receptor-1 (Karlsson et al., 1995). The consensus motif preferentially recognized by the SH2 Introduction domain of Shb was pYTTL (Karlsson et al., 1995), with a strong selection for leucine in position 3 downstream T-cell activation is initiated by the engagement of the from the phosphotyrosine residue. With this knowledge T-cell receptor (TCR) (Weiss and Littman, 1994; in mind, it seemed appropriate to test for Shb- Perlmutter et al., 1993; Chan et al., 1994). This causes interactions in T cells, in which the ITAMs (with a rapid tyrosine phosphorylation of ITAM (immuno- paired YXXL phosphopeptide motifs) play an essential receptor tyrosine-based activation motif) sequences on role in tyrosine kinase dependent signaling. The present data demonstrate the interactions of Shb with ITAM motifs and several other signaling components. We furthermore characterize the central part of Shb as Correspondence: M Welsh, Department of Medical Cell Biology, Box corresponding to a phosphotyrosine binding (PTB) 571, Biomedicum, 75123 Uppsala, Sweden and SE Shoelson, Joslin domain. All three regions of Shb appear signi®cant for Diabetes Center, Harvard Medical School, One Joslin Place, Boston, Shb's interactions in these cells. Together, these results MA, 02215, USA Received 3 July 1997; revised 29 September 1997; accepted 29 suggest that Shb plays an important role for T-cell September 1997 signaling. Shb in T cell signaling MWelshet al 892 the Shb immunoprecipitates were the 55/57 kDa Results phosphoproteins, and next the time-course after CD3 crosslinking for the tyrosine phosphorylation of these Human Shb is expressed in multiple tissues and recruited was studied (Figure 2b). The tyrosine phosphorylation into tyrosine kinase signaling in activated Jurkat cells of the 55/57 kDa products present in the Shb Northern blot analysis of multiple human tissues shows immunoprecipitates rapidly increased (within 30 s) that Shb mRNA is widely expressed as two transcripts and remained elevated for up to 60 min of stimula- of 2.5 and 3.1 kb present in all 16 tissues analysed tion. To assess whether these products corresponded (Figure 1). Mouse tissues contain a predominant 3.1 kb to Shb or were Shb associated, Jurkat cell extracts mRNA (Welsh et al., 1994). Although the levels of from unstimulated or CD3 crosslinked cells were expression were similar in most tissues, prostate boiled in 1% SDS, diluted and subjected to contains slightly more and peripheral blood leukocytes immunoprecipitation with the Shb antibody (Figure somewhat less Shb mRNA (Figure 1). Thus, it is likely 2c). The purpose of this procedure was to disrupt pre- that lymphocytes express the Shb mRNA, since these existing complexes between Shb and other proteins. cells are present in spleen, thymus and blood Western blot analysis of anti-Shb immunoprecipitates leukocytes. under these conditions revealed Shb immunoreactivity To assess a functional role of Shb in T cell corresponding to the molecular weights 55 ± 59 kDa signaling, phosphotyrosine proteins present in anti- (Figure 2c). Probing the same blot with the Shb immunoprecipitates of anti-CD3-stimulated Jur- phosphotyrosine antibody PY-20, revealed the ab- kat T cells were determined (Figure 2a). Phosphotyr- sence of detectable amounts of phosphotyrosine osine proteins of molecular weights 22 kDa, 36/ proteins in these immunoprecipitates, suggesting that 38 kDa, 55/57 kDa, 70 kDa, 100 kDa and 190 kDa the phosphorylated 55/57 products indeed are Shb- were all found to co-precipitate with Shb after TCR associated. One of the supernatants after the anti-Shb stimulation. Although these six phosphotyrosine immunoprecipitation in Figure 2c was transferred to a proteins were commonly seen in the anti-Shb fresh tube and subjected to a second immunoprecipi- immunoprecipitates, their relative abundance varied tation with the Shb antibody (Figure 2c). Shb between dierent experiments (see Figure 3a). The immunoreactivity was absent under these conditions, precipitation of these products was speci®c for the Shb suggesting ecient precipitation of Shb in the ®rst antibody compared with normal rabbit serum (NRS). immunoprecipitation. The results in Figure 2a and b When testing for Shb immunoreactivity, a broad band suggest that Shb is rapidly recruited into tyrosine of 55 ± 59 kDa was observed which was speci®cally kinase signaling upon T cell activation, implying a immunoprecipitated with the Shb antibody (Figure functional role for Shb in this process. 2a). In Jurkat cell extracts, the Shb antibody recognizes in addition to the 55 ± 59 kDa Shb Comparison of Shb and Grb2 co-immunoprecipitation of products present in the immunoprecipitates bands of phosphotyrosine proteins 66, 77 and 80 kDa (see Figure 3d). Previously, Shb isoforms of 55, 66 and 77 kDa have been described, To identify the Shb-associated phosphotyrosine pro- with the 66 kDa product representing Shb initiated at teins, anti-CD3 activated Jurkat cells were lysed and the ®rst methionine codon, the 55 kDa protein Shb proteins co-immunoprecipitated with the Shb or Grb initiated at the second methionine codon and the antibodies were compared. Co-precipitated proteins 77 kDa component probably representing a post- were identi®ed by blotting for phosphotyrosine (Figure translationally modi®ed Shb (Karlsson and Welsh, 3a,b). Tyrosine phosphorylation levels increased 1996). Major phosphotyrosine products observed in following CD3 crosslinking including those of the anti-Shb precipitated proteins of 36/38 kDa, 55 ± 57 kDa, 70 kDa and 190 kDa. The 36/38 kDa, 55/57 and 70 kDa proteins were also immunoprecipitated he br pl lu li sm ki pa sp th pr te ov in co pbl using the Grb2 antibody. The immunoprecipitation of the 36/38 kDa product was more ecient with the Grb2 antibody. Shorter exposure of the ECL reaction also revealed an approximate doubling of the phosphotyrosine content of p36/38 associated with Grb2 in this experiment (results not shown).
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