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• W2005874078 abstract "Genetic studies revealed that CD5 could be a negative regulator of the B-cell antigen receptor (BCR). We explore here the effect of human CD5 on BCR-triggered responses. B cells were obtained expressing a chimera composed of extracellular and transmembrane domains of Fcγ type IIB receptor fused to CD5 cytoplasmic domain (CD5cyt). Coligation of the chimera with the BCR induces CD5cyt tyrosine phosphorylation. A rapid inhibition of BCR-induced calcium response is observed, as well as a partial but delayed inhibition of phospholipase Cγ-1 phosphorylation. Activation of extracellular regulated kinase-2 is also severely impaired. Moreover, at the functional level, interleukin-2 production is abolished. Src homology 2 domain-bearing tyrosine phosphatase SHP-1 and Src homology 2 domain-bearing inositol 5′-phosphatase SHIP usually participate in negative regulation of the BCR. We show that they do not associate with the phosphorylated CD5 chimera. We finally demonstrate that the pseudo-immunoreceptor tyrosine based activation motif present in CD5cyt is involved because its deletion eliminates the inhibitory effect of the chimera, both at biochemical and functional levels. These results demonstrate the inhibitory role of CD5 pseudo-immunoreceptor tyrosine based activation motif tyrosine phosphorylation on BCR signaling. They further support the idea that CD5 uses mechanisms different from those already described to negatively regulate the BCR pathway. Genetic studies revealed that CD5 could be a negative regulator of the B-cell antigen receptor (BCR). We explore here the effect of human CD5 on BCR-triggered responses. B cells were obtained expressing a chimera composed of extracellular and transmembrane domains of Fcγ type IIB receptor fused to CD5 cytoplasmic domain (CD5cyt). Coligation of the chimera with the BCR induces CD5cyt tyrosine phosphorylation. A rapid inhibition of BCR-induced calcium response is observed, as well as a partial but delayed inhibition of phospholipase Cγ-1 phosphorylation. Activation of extracellular regulated kinase-2 is also severely impaired. Moreover, at the functional level, interleukin-2 production is abolished. Src homology 2 domain-bearing tyrosine phosphatase SHP-1 and Src homology 2 domain-bearing inositol 5′-phosphatase SHIP usually participate in negative regulation of the BCR. We show that they do not associate with the phosphorylated CD5 chimera. We finally demonstrate that the pseudo-immunoreceptor tyrosine based activation motif present in CD5cyt is involved because its deletion eliminates the inhibitory effect of the chimera, both at biochemical and functional levels. These results demonstrate the inhibitory role of CD5 pseudo-immunoreceptor tyrosine based activation motif tyrosine phosphorylation on BCR signaling. They further support the idea that CD5 uses mechanisms different from those already described to negatively regulate the BCR pathway. T-cell receptor antibody B-cell receptor CD5 intracellular domain extracellular regulated kinase Fcγ type IIB receptor interleukin-2 immunoreceptor tyrosine-based activation motif immunoreceptor tyrosine-based inhibition motif killer cell inhibitory receptor monoclonal antibody polymerase chain reaction phospholipase C protein-tyrosine kinase rabbit anti-mouse Src homology 2 SH2 domain-bearing inositol 5′-phosphatase SH2 domain-bearing tyrosine phosphatase fluorescein isothiocyanate 4,5-P3, phosphatidylinositol-3,4,5-trisphosphate CD5, a 67-kDa monomeric type I membrane antigen, belongs to a family of proteins widely expressed by cells of the immune system and whose extracellular domains are characterized by the presence of the highly conserved scavenger receptor cysteine-rich domain (1Resnick D. Pearson A. Krieger M. Trends Biochem Sci. 1994; 19: 5-8Abstract Full Text PDF PubMed Scopus (309) Google Scholar). CD5 has several potential ligands (2Van de Velde H.I. von Hoegen I. Luo W. Parnes J.R. Thielemans K. Nature. 1991; 351: 662-665Crossref PubMed Scopus (278) Google Scholar, 3Biancone L. Bowen M.A. Lim A. Aruffo A. Andres G. Stamenkovic I. J. Exp. Med. 1996; 184: 811-819Crossref PubMed Scopus (90) Google Scholar, 4Pospisil R. Fitts M.G. Mage R.G. J. Exp. Med. 1996; 184: 1279-1284Crossref PubMed Scopus (75) Google Scholar). The best known is CD72, an homodimeric membrane glycoprotein commonly present on B cells (2Van de Velde H.I. von Hoegen I. Luo W. Parnes J.R. Thielemans K. Nature. 1991; 351: 662-665Crossref PubMed Scopus (278) Google Scholar). CD5 is expressed on T and B cells. Most immature T cells express the molecule, including earliest precursors. Thereafter, CD5 levels are coordinately up-regulated with cell surface CD3 (5Weiss A. Dazin P.F. Shields R. Fu S.M. Lanier L.L. J. Immunol. 1987; 139: 3245-3250PubMed Google Scholar). At the periphery, all T cells express high levels of CD5. On the contrary, CD5 is not present on all B cells (6Hayakawa K. Hardy R.R. Park D.R. Herzenberg L.A. J. Exp. Med. 1983; 157: 202-218Crossref PubMed Scopus (666) Google Scholar). On the basis of its co-expression with CD11b, a molecule of the integrin family, IgM+ B cells can be separated in different subsets usually termed B-1a, B-1b, and B2 (7Herzenberg L.A. Stall A.M. Lalor P.A. Sidman C. Moore W.A. Parks D.R. Immunol. Rev. 1986; 93: 81-102Crossref PubMed Scopus (555) Google Scholar, 8Hayakawa K. Hardy R.R. Annu. Rev. Immunol. 1988; 6: 197-218Crossref PubMed Scopus (305) Google Scholar, 9Kipps T.J. Adv. Immunol. 1989; 47: 117-185Crossref PubMed Scopus (302) Google Scholar, 10Kantor A.B. Immunol. Today. 1991; 12: 389-392Abstract Full Text PDF PubMed Scopus (182) Google Scholar). Only the B-1a subset expresses CD5. B-1a cells have unusual properties (reviewed in Ref. 11Tarakhovsky A. J. Exp. Med. 1997; 185: 981-984Crossref PubMed Scopus (36) Google Scholar) such as self-renewal capacity. They constitute a substantial fraction of the peritoneal and pleural mouse B cells.It has long been known that in T lymphocytes a proportion of CD5 associates with the T-cell receptor (TCR)1 at the membrane (12Burgess K.E. Yamamoto M. Prasad K.V. Rudd C.E. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9311-9315Crossref PubMed Scopus (108) Google Scholar,13Osman N. Ley S.C. Crumpton M.J. Eur. J. Immunol. 1992; 22: 2995-3000Crossref PubMed Scopus (48) Google Scholar). CD5 effect on TCR-mediated responses remained, however, elusive until the establishment of CD5-knockout mice. In the absence of CD5, immature T cells were hyperresponsive to TCR stimulation in vitro (14Tarakhovsky A. Kanner S.B. Hombach J. Ledbetter J.A. Müller W. Killeen N. Rajewsky K. Science. 1996; 269: 535-537Crossref Scopus (360) Google Scholar). Increased proliferation and, at the signaling level, increased tyrosine phosphorylation of phospholipase C (PLC) γ-1, LAT (linker for activation of T cells), and Vav associated with increased Ca2+ response were observed. An increased expression of the fully tyrosine phosphorylated p23 species of the TCRζ chain that adequately recruits and activates the protein-tyrosine kinase (PTK) ZAP-70 was also noticed. Accordingly, a possible critical role for CD5 in regulating the phosphorylation state of ζ was also reported in human thymocytes (15Gary-Gouy H. Lang V. Sarun S. Boumsell L. Bismuth G. J. Immunol. 1997; 159: 3739-3747PubMed Google Scholar). Thus, it was proposed that CD5 may negatively influence the activity of critical signaling elements between the TCR and the Ca2+ response, particularly in immature T cells. The cytoplasmic domain of CD5 is tyrosine phosphorylated after TCR engagement (12Burgess K.E. Yamamoto M. Prasad K.V. Rudd C.E. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 9311-9315Crossref PubMed Scopus (108) Google Scholar, 16Davies A.A. Ley S.C. Crumpton M.J. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 6368-6372Crossref PubMed Scopus (78) Google Scholar, 17Raab M. Yamamoto M. Rudd C.E. Mol. Cell. Biol. 1994; 14: 2862-2870Crossref PubMed Google Scholar). It was therefore assumed that this phenomenon may help to recruit Src homology 2 (SH2) domain-containing signaling molecules with inhibitory properties. Notably, an implication of the SH2 domain-bearing tyrosine phosphatase SHP-1 was predicted. SHP-1 is known to exert a negative influence on the early tyrosine phosphorylation events elicited by TCR activation (18Plas D.R. Johnson R. Pingel J.T. Matthews R.J. Dalton M. Roy G. Chan A.C. Thomas M.L. Science. 1996; 272: 1173-1176Crossref PubMed Scopus (329) Google Scholar, 19Raab M. Rudd C.E. Biochem. Biophys. Res. Commun. 1996; 222: 50-57Crossref PubMed Scopus (37) Google Scholar), and it was reported to associate with CD5 in murine thymocytes (20Pani G. Fischer K.D. Mlinaric-Rascan I. Siminovitch K.A. J. Exp. Med. 1996; 184: 839-852Crossref PubMed Scopus (179) Google Scholar). Moreover, an association of SHP-1 that requires a tyrosine residue (at position 378) in an immunoreceptor tyrosine based inhibition motif (ITIM)-like sequence straddling the transmembrane and the cytoplasmic domain of CD5 was also described in Jurkat T cells (21Perez-Villar J.J. Whitney G.S. Bowen M.A. Hewgill D.H. Aruffo A.A. Kanner S.B. Mol. Cell. Biol. 1999; 19: 2903-2912Crossref PubMed Scopus (146) Google Scholar).CD5 is also associated with the B-cell receptor (BCR) (22Lankester A.C. van Schijndel G.M.W. Cordell J.L. van Noesel C.J.M. van Lier R.A.W. Eur. J. Immunol. 1994; 24: 812-816Crossref PubMed Scopus (101) Google Scholar), and studies in CD5-deficient mice also suggested a negative role of the molecule on BCR signaling. Normal CD5+ peritoneal B-1 cells proliferate poorly in response to an anti-μ stimulation. Proliferation was restored in CD5-negative mice (23Bikah G. Carey J. Ciallella J.R. Tarakhovsky A. Bondada S. Science. 1996; 274: 1906-1909Crossref PubMed Scopus (259) Google Scholar). Ca2+ response also increased in parallel. Thus, CD5 molecules may also down-regulate some early signaling events of the BCR biochemical pathway. In agreement with this assumption was the finding that a previous cross-linking of CD5 on normal B-1 cells could restore anti-IgM-induced proliferation, likely by moving these molecules away from the BCR (23Bikah G. Carey J. Ciallella J.R. Tarakhovsky A. Bondada S. Science. 1996; 274: 1906-1909Crossref PubMed Scopus (259) Google Scholar). However, no direct evidence has been yet provided showing that CD5 could inhibit early signaling events triggered through the BCR. The present study was undertaken to investigate this possibility.To analyze the regulatory properties of CD5 on BCR signaling, we expressed in a murine B cell line a chimeric membrane receptor made of the cytoplasmic domain of CD5 (CD5cyt), beginning at residue lysine 379, with the extracellular and transmembrane domains of the low affinity IgG receptor FcγRIIB. Our results demonstrate that when coligated with the BCR, the CD5 chimera strongly antagonized both biochemical and functional BCR stimulatory events. They also show the key role played by the cytoplasmic sequence of CD5, which comprises two tyrosine residues in a pseudo-immunoreceptor tyrosine based activation motif (ITAM). They further suggest that the inhibitory action of CD5 is mediated by different molecules in B cells and T cells because our results show no clear implication of SHP-1.DISCUSSIONOnly few studies investigated the signaling properties of CD5 in B cells. As with its T-cell counterpart, a privileged physical link between CD5 and the B-cell antigen-specific receptor in CD5+ B cells was demonstrated (22Lankester A.C. van Schijndel G.M.W. Cordell J.L. van Noesel C.J.M. van Lier R.A.W. Eur. J. Immunol. 1994; 24: 812-816Crossref PubMed Scopus (101) Google Scholar). Several reports also suggested a possible cooperation between the two receptors at the functional level leading to the hypothesis that CD5 positively contributes to B cell activation (41Cerutti A. Trentin L. Zambello R. Sancetta R. Milani A. Tassinari C. Adami F. Agostini C. Semenzato G. J. Immunol. 1996; 157: 1854-1862PubMed Google Scholar, 42Jamin C. Le Corre R. Lydyard P.M. Youinou P. Eur. J. Immunol. 1996; 26: 57-62Crossref PubMed Scopus (21) Google Scholar). Other arguments arising from studies in CD5 knockout mice promote instead a negative role of CD5 on BCR-induced responses. To further elucidate this problem, we studied in a murine B cell model the consequences of coligation of BCR with CD5 on BCR-mediated responses.The IIA1.6 murine B cell model, a FcγRIIB-negative variant of the A20 lymphoma B cell line, is ideally suited to analyze the effects of receptors that may interfere with BCR signaling. Indeed, by constructing a chimeric molecule containing the extracellular domain of FcγRIIB and the cytoplasmic domain of the receptor, one can use a straightforward procedure to bring into close contact the chimera with the BCR using a single Ab. We therefore used this system to investigate the effects of CD5 on BCR stimulatory events. Our results unambiguously demonstrate an inhibition of B cell activation by the cytoplasmic domain of CD5. Striking effects were especially observed at the functional level because IL-2 synthesis was suppressed by CD5. This was explained by our parallel observations that, at the biochemical level, both Ca2+ and Ras activation pathways activated through the BCR were strongly antagonized upon coligation with the chimera.BCR-induced Ca2+ responses were negatively controlled by CD5 after coligation of the two receptors. The initial Ca2+rise was identical with RAM IgG or RAM F(ab′)2 fragments, but it was abruptly stopped a few seconds later and returned rapidly to basal levels (Fig. 2). We found in parallel a partial reduction of PLCγ-1 phosphorylation that could explain this Ca2+inhibition. However, kinetic studies showed that induction of PLCγ-1 phosphorylation was not affected at this early time course. We even found an increased phosphorylation for short periods of stimulation with whole IgG. Thus, inhibition of PLCγ-1 metabolism may be not the primary event. The measure of other parameters of PLCγ-1 activation is now under progress to clarify this point. An inhibitory effect of CD5 on TCR-induced Ca2+ responses in Jurkat T cells was recently reported after coligation of CD5 with the CD3 molecule (21Perez-Villar J.J. Whitney G.S. Bowen M.A. Hewgill D.H. Aruffo A.A. Kanner S.B. Mol. Cell. Biol. 1999; 19: 2903-2912Crossref PubMed Scopus (146) Google Scholar). Experiments in Ca2+-free medium were not performed. However, the obtained Ca2+ profiles suggested no or poor inhibition of the sustained Ca2+ influx phase by CD5. On the contrary, we found a severe inhibition of Ca2+ influx in our B cell model. Sustained Ca2+ influx phase is crucial to trigger transcription of various genes in lymphocytes, like the IL-2 gene (43Crabtree G.R. Cell. 1999; 96: 611-614Abstract Full Text Full Text PDF PubMed Scopus (661) Google Scholar). This ultimately suggests that the outcome of CD5-mediated inhibition may be more severe in B cells than in T cells. Accordingly, CD5 seems to have a stronger effect on BCR-induced proliferation, as illustrated in mice by the results obtained with B1a cells whose proliferation is restored in CD5 knockout animals or, more spectacularly, after keeping CD5 well away from the BCR (23Bikah G. Carey J. Ciallella J.R. Tarakhovsky A. Bondada S. Science. 1996; 274: 1906-1909Crossref PubMed Scopus (259) Google Scholar).Coligation of the FcγRIIB-CD5 chimera with BCR induced a strong tyrosine phosphorylation of CD5cyt. The Src PTK Lyn is presumably involved because it has already been shown to be responsible for FcγRIIB1 phosphorylation in similar stimulatory conditions in mast cells (40Malbec O. Fong D.C. Turner M. Tybulewicz V.L. Cambier J.C. Fridman W.H. Daeron M. J. Immunol. 1998; 160: 1647-1658PubMed Google Scholar). The B-cell coreceptor CD22 is also phosphorylated by Lyn (44Smith K.G.C. Tarlinton D.M. Doody G.M. Hibbs M.L. Fearon D.T. J. Exp. Med. 1998; 187: 807-811Crossref PubMed Scopus (221) Google Scholar). This phosphorylation of CD5 is likely required to observe the inhibitory effect. This is in agreement with our observations using the YSQPX 8YPAL CD5 deletant together with the general scheme explaining how cell surface antigens, using particular motifs of their cytoplasmic domain, the so-called ITIM sequences, inhibit neighboring activation receptors. Tyrosine phosphorylated ITIMs recruit SH2-containing phosphatases switching off the activity of PTKs and/or dephosphorylating key downstream elements of the response (reviewed in Refs. 45Unkeless J.C. Jin J. Curr. Opin. Immunol. 1997; 9: 338-343Crossref PubMed Scopus (126) Google Scholar and 46Vivier E. Daëron M. Immunol. Today. 1997; 18: 286-291Abstract Full Text PDF PubMed Scopus (326) Google Scholar). Whether phosphorylated tyrosine residues inside CD5cyt may also represent docking sites for SH2-containing phosphatases was therefore an important question.SHP-1 is a cytosolic tyrosine phosphatase, widely expressed in hematopoietic cells. SHP-1 exerts a negative regulatory influence on the early tyrosine phosphorylation events elicited after activation of different tyrosine kinase-associated receptors, like the TCR (18Plas D.R. Johnson R. Pingel J.T. Matthews R.J. Dalton M. Roy G. Chan A.C. Thomas M.L. Science. 1996; 272: 1173-1176Crossref PubMed Scopus (329) Google Scholar, 19Raab M. Rudd C.E. Biochem. Biophys. Res. Commun. 1996; 222: 50-57Crossref PubMed Scopus (37) Google Scholar) or the BCR (47Cyster J.G. Goodenow C.C. Immunity. 1995; 2: 13-24Abstract Full Text PDF PubMed Scopus (349) Google Scholar, 48Pani G. Kozlowski M. Cambier J.C. Mills G.B. Siminovitch K.A. J. Exp. Med. 1995; 181: 2077-2084Crossref PubMed Scopus (240) Google Scholar). By means of its two SH2 domains, SHP-1 binds to the phosphorylated tyrosine of the ITIM motifs present in the cytoplasmic domain of various inhibitory receptors, for example molecules of the KIR family in NK cells (49Campbell K.S. Dessing M. Lopez-Botet M. Cella M. Colonna M. J. Exp. Med. 1996; 184: 93-100Crossref PubMed Scopus (194) Google Scholar, 50Fry A.M. Lanier L.L. Weiss A. J. Exp. Med. 1996; 184: 295-300Crossref PubMed Scopus (187) Google Scholar) or CD22 (32Doody G.M. Justement L.B. Delibrias C.C. Matthews R.J. Lin J. Thomas M.L. Fearon D.T. Science. 1995; 269: 242-244Crossref PubMed Scopus (483) Google Scholar, 33Law C.L. Sidorenko S.P. Chandran K.A. Zhao Z.H. Shen S.H. Fischer E.H. Clark E.A. J. Exp. Med. 1996; 183: 547-560Crossref PubMed Scopus (176) Google Scholar, 51Nitschke L. Carsetti R. Ocker B. Kohler G. Lamers M.C. Curr. Biol. 1997; 7: 133-143Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar,52Cornall R.J. Cyster J.G. Hibbs M.L. Dunn A.R. Otipoby K.L. Clark E.A. Goodnow C.C. Immunity. 1998; 8: 497-508Abstract Full Text Full Text PDF PubMed Scopus (374) Google Scholar) and PIR-B (53Blery M. Kubagawa H. Chen C.C. Vely F. Cooper M.D. Vivier E. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 2446-2451Crossref PubMed Scopus (176) Google Scholar) in B cells. Its participation in the inhibitory effects of these receptors is now well accepted, raising the possibility that SHP-1 is also involved in the effects of CD5. This question has been addressed for the first time by Pani et al. (20Pani G. Fischer K.D. Mlinaric-Rascan I. Siminovitch K.A. J. Exp. Med. 1996; 184: 839-852Crossref PubMed Scopus (179) Google Scholar) in TCR-activated murine thymocytes. They showed that CD5 became heavily phosphorylated after TCR stimulation, and they detected SHP-1 in CD5 immunoprecipitates. However, SHP-1 was also associated with CD5 in resting thymocytes where CD5 was not significantly phosphorylated, suggesting a mechanism not involving SH2-ITIM interaction. In a recent work performed in Jurkat human T cells, an interaction of SHP-1 with CD5, increased after TCR stimulation, was also reported (21Perez-Villar J.J. Whitney G.S. Bowen M.A. Hewgill D.H. Aruffo A.A. Kanner S.B. Mol. Cell. Biol. 1999; 19: 2903-2912Crossref PubMed Scopus (146) Google Scholar). Especially, it was shown that a particular tyrosine residue of CD5, Tyr378, in an ITIM-like motif, was crucial for the binding of SHP-1 and the inhibition of T cell activation mediated by CD5.However, our results show that the effect of CD5 on BCR signaling is independent of SHP-1 for several reasons. First, and importantly, this tyrosine residue, which is in a very charged region of the molecule just at the junction of transmembrane and cytoplasmic domains, was missing in our CD5 chimera. Second, we did not observe any coprecipitation of SHP-1 with the phosphorylated FcγRIIB-CD5 chimera in IIA 1.6 transfected cells. We cannot exclude that a faint amount of SHP-1, not detectable in our assay conditions, is present. A supplementary argument, however, does not support this possibility. Indeed, experiments made with phosphopeptides of CD5cyt showed that the SH2 domains of SHP-1 did not bind to any CD5cyt phosphopeptides (54Dennehy K.M. Broszeit R. Ferris W.F. Beyers A.D. Eur. J. Immunol. 1998; 28: 1617-1625Crossref PubMed Scopus (35) Google Scholar). Interestingly, we can notice from the sequence of CD5 (Fig. 1) that a particular motif, with a serine in position −2 (SAYPAL), is also present inside the pseudo-ITAM. It is different from the prototypal inhibitory sequence (I/V)XYXX(L/V) found in most inhibitory receptors. Nevertheless, this motif is present in the mast cell function-associated antigen, a murine inhibitory co-receptor member of the C-type lectin family where the I/V residue at position −2 is replaced by a serine residue (55Guthmann M.D. Tal M. Pecht I. Proc. Natl. Acad. Sci. U. S. A. 1995; 92: 9397-9401Crossref PubMed Scopus (87) Google Scholar). Thus, we also controlled with a phosphorylated peptide of the pseudo-ITAM that this sequence did not precipitate SHP-1 or SHP-2 from lysates of the lymphoma B cells (data not shown). As a supplementary argument, it should be emphasized that in IIA 1.6 B cells, inhibitory chimeric receptors that recruit SHP-1, such as those containing the cytoplasmic domain of a KIR, abolished the Ca2+ mobilization phase (39Bruhns P. Marchetti P. Fridman W.H. Vivier E. Daeron M. J. Immunol. 1999; 162: 3168-3175PubMed Google Scholar). This phase is weakly inhibited by CD5, suggesting again a distinct mechanism. This also agrees with our observation that phosphorylation of PLCγ-1 is not impaired by CD5 at the initial phase of the response (Fig. 2 B).Phosphorylated FcγRIIB recruits SHIP in vivo (34Ono M. Bolland S. Tempst P. Ravetch J.V. Nature. 1996; 383: 263-266Crossref PubMed Scopus (644) Google Scholar, 35D'Ambrosio D. Fong D.C. Cambier J.C. Immunol. Lett. 1996; 54: 77-82Crossref PubMed Scopus (85) Google Scholar, 36Gupta N. Scharenberg A.M. Burshtyn D.N. Wagtmann N. Lioubin M.N. Rohrschneider L.R. Kinet J.P. Long E.O. J. Exp. Med. 1997; 186: 473-478Crossref PubMed Scopus (74) Google Scholar, 37Vely F. Olivero S. Olcese L. Moretta A. Damen J.E. Liu L. Krystal G. Cambier J.C. Daeron M. Vivier E. Eur. J. Immunol. 1997; 27: 1994-2000Crossref PubMed Scopus (122) Google Scholar). SHIP is a signal transduction molecule with inositol polyphosphate-5-phosphatase activity (56Lioubin M.N. Algate P.A. Tsai S. Carlberg K. Aebersold A. Rohrschneider L.R. Genes Dev. 1996; 10: 1084-1095Crossref PubMed Scopus (378) Google Scholar). One proposed target for SHIP is phosphatidylinositol-3,4,5-trisphosphate (PI-3,4,5-P3) (57Scharenberg A.M. El-Hillal O. Fruman D.A. Beitz L.O. Li Z. Lin S. Gout I. Cantley L.C. Rawlings D.J. Kinet J.P. EMBO J. 1998; 17: 1961-1972Crossref PubMed Scopus (386) Google Scholar). PI-3,4,5-P3 mediates the translocation to the plasma membrane of important signaling molecules for the Ca2+response containing a PI-3,4,5-P3-binding PH domain, like the Bruton's tyrosine kinase (58Takata M. Kurosaki T. J. Exp. Med. 1996; 184: 31-40Crossref PubMed Scopus (424) Google Scholar). Thus SHIP could impair Ca2+ responses by regulating membrane association of Bruton's tyrosine kinase (59Bolland S. Pearse R.N. Kurosaki T. Ravetch J.V. Immunity. 1998; 8: 509-516Abstract Full Text Full Text PDF PubMed Scopus (324) Google Scholar). Moreover, a competitive role was also proposed for SHIP in blocking the interaction of Shc with the Grb2-Sos complex of proteins that lead to Ras activation in B cells (60Tridandapani S. Chacko G.W. Van Brocklyn J.R. Coggeshall K.M. J. Immunol. 1997; 158: 1125-1132PubMed Google Scholar, 61Tridandapani S. Pradhan M. LaDine J.R. Garber S. Anderson C.L. Coggeshall K.M. J. Immunol. 1999; 162: 1408-1414PubMed Google Scholar). CD5 inhibitory effects seem to be very close from those triggered by FcγRIIB1, suggesting an identical inhibitory mechanism. Thus, quite similar Ca2+ profiles were obtained upon coligation of BCR with either receptors, and we report a strong inhibition of Ras pathway by CD5. However, we did not find any recruitment of SHIP by the phosphorylated chimera in coprecipitation experiments (Fig. 4 B) or by the phosphorylated CD5 peptides (not shown). This prompted us to conclude that the mechanism responsible for the inhibition by CD5 of BCR activation in IIA1.6 murine B cells was also independent of SHIP. Other inhibitory phosphates may exist, and we did not check yet the new inositol 5-phosphatase SHIP2 showing homology with SHIP (62Pesesse X. Deleu S. De Smedt F. Drayer L. Erneux C. Biochem. Biophys. Res. Commun. 1997; 239: 697-700Crossref PubMed Scopus (199) Google Scholar).Obviously, molecules with other biological activities may be responsible. After TCR stimulation, CD5 is phosphorylated on tyrosine but also, heavily, on serine residue (16Davies A.A. Ley S.C. Crumpton M.J. Proc. Natl. Acad. Sci. U. S. A. 1992; 89: 6368-6372Crossref PubMed Scopus (78) Google Scholar). The cytoplasmic tail of CD5 contains at least five consensus sites for serine/threonine phosphorylation. No clear function was assigned for these phosphorylations in the physiology of CD5, but a serine kinase activity, increased after CD3 stimulation, is immunoprecipitated with CD5 in peripheral blood mononuclear cells (63Alberola-Ila J. Places L. Lozano F. Vives J. J. Immunol. 1993; 151: 4423-4430PubMed Google Scholar). Moreover, a constitutive phosphorylation of CD5 on serine residues 459 and 461 has been reported that can be involved in the regulation of phosphatidylcholine-PLC metabolism by the receptor (64Simarro M. Pelassy C. Calvo J. Places L. Aussel C. Lozano F. J. Immunol. 1997; 159: 4307-4315PubMed Google Scholar). More recently, association of CD5 with different serine kinases, like casein kinase II (65Calvo J. Vilda J.M. Places L. Simarro M. Padilla O. Andreu D. Campbell K.S. Aussel C. Lozano F. J. Immunol. 1998; 161: 6022-6029PubMed Google Scholar) or Ca2+/calmodulin-dependent kinases (66Gringhuis S.I. de Leij L.F.M.H. Wayman G.A. Tokumitsu H. Vellenga E. J. Biol. Chem. 1997; 272: 31809-31820Abstract Full Text Full Text PDF PubMed Scopus (40) Google Scholar,67Bauch A. Campbell K.S. Reth M. Eur J Immunol. 1998; 28: 2167-2177Crossref PubMed Scopus (39) Google Scholar), was reported. CD5 also activates in T cells acidic sphingomyelinase, protein kinase C-ζ, mitogen-activated protein kinase kinase, and c-Jun NH2-terminal kinase (68Simarro M. Calvo J. Vila J.M. Places L. Padilla O. Alberola-Ila J. Vives J. Lozano F. J. Immunol. 1999; 162: 5149-5155PubMed Google Scholar). A role for these different pathways, especially those linked to serine phosphorylation of CD5, is therefore disputable to explain its inhibitory action. Our results showed, however, that the pseudo ITAM of CD5 was necessary, suggesting a mechanism governed by phosphorylated tyrosine residues. Importantly, this phosphorylated motif binds different signaling molecules like phosphatidylinositol 3-kinase, Ras GTPase-activating protein, and, undirectly, the proto-oncoprotein c-Cbl (54Dennehy K.M. Broszeit R. Ferris W.F. Beyers A.D. Eur. J. Immunol. 1998; 28: 1617-1625Crossref PubMed Scopus (35) Google Scholar, 69Dennehy K.M. Broszeit R. Garnett D. Durrheim G.A. Spruyt L.L. Beyers A.D. Eur. J. Immunol. 1997; 27: 679-686Crossref PubMed Scopus (42) Google Scholar). Much speculation can be made how recruitment of these molecules on phosphorylated CD5 within a CD5-BCR complex may hinder the normal functioning of BCR signaling cascade. But phosphatidylinositol 3-kinase is essential for B cell development and proliferation (70Fruman D.A. Snapper S.B. Yballe C.M. Davidson L. Yu J.Y. Alt F.W. Cantley L.C. Science. 1999; 283: 393-397Crossref PubMed Scopus (568) Google Scholar). A critical role is also likely played by c-Cbl because the molecule can negatively regulate Syk PTK (71Lupher Jr., M.L. Rao N. Lill N.L. Andoniou C.E. Miyake S. Clark E.A. Druker B. Band H. J. Biol. Chem. 1998; 273: 35273-35281Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar, 72Ota Y. Samelson L.E. Science. 1997; 276: 418-420Crossref PubMed Scopus (225) Google Scholar) and interacts in vivowith numerous other signaling molecules like Fyn, Grb2, and Shc, the p85 subunit of phosphatidylinositol 3-kinase (73Fukazawa T. Reedquist K.A. Trub T. Soltoff S. Panchamoorthy G. Druker B. Cantley L. Shoelson S.E. Band H. J. Biol. Chem. 1995; 270: 19141-19150Abstract Full Text Full Text PDF PubMed Scopus (186) Google Scholar, 74Panchamoorthy G. Fukazawa T. Miyake S. Soltoff S. Reedquist K. Druker B. Shoelson S. Cantley L. Band H. J. Biol. Chem. 1996; 271: 3187-3194Crossref PubMed Scopus (176) Google Scholar, 75Hartley D. Corvera S. J. Biol. Chem. 1996; 271: 21939-21943Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar) as well as the SH3 domain of Bruton's tyrosine kinase (76Cory G.O.C. Lovering R.C. Hinshelwood S. MacCarthy-Morrogh L. Levinsky R.J. Kinnon C. J. Exp. Med. 1995; 182: 611-615Crossref PubMed Scopus (126) Google Scholar). By altering BCR targeting of such key signaling molecules, CD5 may therefore profoundly influence signaling downstream of the BCR. CD5, a 67-kDa" @default.
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• W2005874078 title "The Pseudo-immunoreceptor Tyrosine-based Activation Motif of CD5 Mediates Its Inhibitory Action on B-cell Receptor Signaling" @default.
• W2005874078 cites W1533289349 @default.
• W2005874078 cites W1535592595 @default.
• W2005874078 cites W1547318123 @default.
• W2005874078 cites W1576525631 @default.
• W2005874078 cites W1578284751 @default.
• W2005874078 cites W1600515349 @default.
• W2005874078 cites W1627612497 @default.
• W2005874078 cites W1658761436 @default.
• W2005874078 cites W1977128317 @default.
• W2005874078 cites W1978884666 @default.
• W2005874078 cites W1979769420 @default.
• W2005874078 cites W1980776953 @default.
• W2005874078 cites W1981863728 @default.
• W2005874078 cites W1982025355 @default.
• W2005874078 cites W1982833418 @default.
• W2005874078 cites W1984838238 @default.
• W2005874078 cites W1993176549 @default.
• W2005874078 cites W1999932257 @default.
• W2005874078 cites W2000182583 @default.
• W2005874078 cites W2004756723 @default.
• W2005874078 cites W2006095839 @default.
• W2005874078 cites W2008065206 @default.
• W2005874078 cites W2009082398 @default.
• W2005874078 cites W2017355451 @default.
• W2005874078 cites W2017516492 @default.
• W2005874078 cites W2024000365 @default.
• W2005874078 cites W2028920820 @default.
• W2005874078 cites W2030793757 @default.
• W2005874078 cites W2032468105 @default.
• W2005874078 cites W2035277099 @default.
• W2005874078 cites W2036007339 @default.
• W2005874078 cites W2045995507 @default.
• W2005874078 cites W2046062797 @default.
• W2005874078 cites W2051774115 @default.
• W2005874078 cites W2052249831 @default.
• W2005874078 cites W2053142169 @default.
• W2005874078 cites W2056462157 @default.
• W2005874078 cites W2061241669 @default.
• W2005874078 cites W2063825367 @default.
• W2005874078 cites W2069132486 @default.
• W2005874078 cites W2069545269 @default.
• W2005874078 cites W2070666617 @default.
• W2005874078 cites W2076317552 @default.
• W2005874078 cites W2079923162 @default.
• W2005874078 cites W2082502466 @default.
• W2005874078 cites W2088551118 @default.
• W2005874078 cites W2090392995 @default.
• W2005874078 cites W2090904163 @default.
• W2005874078 cites W2091259187 @default.
• W2005874078 cites W2091495230 @default.
• W2005874078 cites W2099905259 @default.
• W2005874078 cites W2100877501 @default.
• W2005874078 cites W2101073455 @default.
• W2005874078 cites W2105542965 @default.
• W2005874078 cites W2108524870 @default.
• W2005874078 cites W2114245938 @default.
• W2005874078 cites W2128587758 @default.
• W2005874078 cites W2133226508 @default.
• W2005874078 cites W2141260882 @default.
• W2005874078 cites W2144005905 @default.
• W2005874078 cites W2144225361 @default.
• W2005874078 cites W2144954864 @default.
• W2005874078 cites W2145589602 @default.
• W2005874078 cites W2146953988 @default.
• W2005874078 cites W2149827890 @default.
• W2005874078 cites W2156587144 @default.
• W2005874078 cites W2165023381 @default.
• W2005874078 cites W2165742826 @default.
• W2005874078 cites W2165835604 @default.
• W2005874078 cites W4293168410 @default.
• W2005874078 cites W4313308252 @default.
• W2005874078 cites W4313333705 @default.
• W2005874078 cites W4313333797 @default.
• W2005874078 cites W4313404944 @default.
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