Expression of CD45 Lacking the Catalytic Protein Tyrosine Phosphatase Domain Modulates Lck Phosphorylation and T Cell Activation

The function of the second protein tyrosine phosphatase domain (D2) in two-domain protein tyrosine phosphatases (PTP) is not well understood. In CD45, D2 can interact with the catalytic domain (D1) and stabilize its activity. Although D2 itself has no detectable catalytic activity, it can bind substrate and may influence the substrate specificity of CD45. To further explore the function of D2 in T cells, a full-length construct of CD45 lacking the D1 catalytic domain (CD45RABC-D2) was expressed in CD45+ and CD45− Jurkat T cells. In CD45− Jurkat T cells, CD45RABC-D2 associated with Lck but, unlike its active counterpart CD45RABC, did not restore the induction of tyrosine phosphorylation or CD69 expression upon T cell receptor (TCR) stimulation. Expression of CD45RABC-D2 in CD45+ Jurkat T cells resulted in its association with Lck, increased the phosphorylation state of Lck, and reduced T cell activation. TCR-induced tyrosine phosphorylation was delayed, and although MAPK phosphorylation and CD69 expression were not significantly affected, the calcium signal and IL2 production were severely reduced. This indicates that the non-catalytic domains of CD45 can interact with Lck in T cells. CD45RABC-D2 acts as a dominant negative resulting in an increase in Lck phosphorylation and a preferential loss of the calcium signaling pathway, but not the MAPK pathway, upon TCR signaling. This finding suggests that, in addition to their established roles in the initiation of TCR signaling, CD45 and Lck may also influence the type of TCR signal generated. The function of the second protein tyrosine phosphatase domain (D2) in two-domain protein tyrosine phosphatases (PTP) is not well understood. In CD45, D2 can interact with the catalytic domain (D1) and stabilize its activity. Although D2 itself has no detectable catalytic activity, it can bind substrate and may influence the substrate specificity of CD45. To further explore the function of D2 in T cells, a full-length construct of CD45 lacking the D1 catalytic domain (CD45RABC-D2) was expressed in CD45+ and CD45− Jurkat T cells. In CD45− Jurkat T cells, CD45RABC-D2 associated with Lck but, unlike its active counterpart CD45RABC, did not restore the induction of tyrosine phosphorylation or CD69 expression upon T cell receptor (TCR) stimulation. Expression of CD45RABC-D2 in CD45+ Jurkat T cells resulted in its association with Lck, increased the phosphorylation state of Lck, and reduced T cell activation. TCR-induced tyrosine phosphorylation was delayed, and although MAPK phosphorylation and CD69 expression were not significantly affected, the calcium signal and IL2 production were severely reduced. This indicates that the non-catalytic domains of CD45 can interact with Lck in T cells. CD45RABC-D2 acts as a dominant negative resulting in an increase in Lck phosphorylation and a preferential loss of the calcium signaling pathway, but not the MAPK pathway, upon TCR signaling. This finding suggests that, in addition to their established roles in the initiation of TCR signaling, CD45 and Lck may also influence the type of TCR signal generated. CD45 is a transmembrane two-domain protein tyrosine phosphatase (PTP) 1The abbreviations used are: PTP, protein tyrosine phosphatase; IL, interleukin; CD45RABC-D2, containing extracellular RABC isoform, transmembrane region, membrane proximal region, the second PTP domain, and carboxyl tail; FACS, fluorescence-activated cell sorter; PLC, phospholipase C; MAPK, mitogen-activated protein kinase; J+, Jurkat leukemia T cell line, clone E6.1 (CD45 positive); J−, Jurkat leukemia T cell line, clone 45.01 (CD45 negative); Ab, antibody; mAb, monoclonal antibody; IP3, inositol 1,4,5-trisphosphate; PVDF, polyvinylidene difluoride; TCR, T cell antigen receptor; HRP, horseradish peroxidase; FITC, fluorescein isothiocyanate; ERK, extracellular signal-regulated kinase; LAR, leukocyte antigen-related protein. expressed exclusively in leukocytes (reviewed in Refs. 1.Thomas M.L. Annu. Rev. Immunol. 1989; 7: 339-369Crossref PubMed Google Scholar, 2.Trowbridge I.S. Thomas M.L. Annu. Rev. Immunol. 1994; 12: 85-116Crossref PubMed Scopus (666) Google Scholar, 3.Johnson P. Maiti A. Ng D.H.W. Herzenberg L.A. Weir D.M. Herzenberg L.A. Blackwell C. Weir's Handbook of Experimental Immunology. 5th Ed. II. Blackwell Science, Inc., Malden, MA1997: 62.61Google Scholar, 4.Hermiston M.L. Xu Z. Weiss A. Annu. Rev. Immunol. 2003; 21: 107-137Crossref PubMed Scopus (667) Google Scholar). There are 21 transmembrane PTP in the human genome, and 12 have two domains (5.Alonso A. Sasin J. Bottini N. Friedberg I. Osterman A. Godzik A. Hunter T. Dixon J. Mustelin T. Cell. 2004; 117: 699-711Abstract Full Text Full Text PDF PubMed Scopus (1549) Google Scholar). The catalytic activity of CD45 and other transmembrane two-domain PTP, such as PTPα and LAR, resides primarily in the first membrane proximal PTP with little or no activity attributed to the second PTP domain, D2 (6.Walton K.M. Dixon J.E. Ann. Rev. Biochem. 1993; 62: 101-120Crossref PubMed Scopus (416) Google Scholar). In the case of CD45, the majority of data indicate that D2 is inactive (7.Felberg J. Johnson P. J. Biol. Chem. 1998; 273: 17839-17845Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 8.Johnson P. Ostergaard H.L. Wasden C. Trowbridge I.S. J. Biol. Chem. 1992; 267: 8035-8041Abstract Full Text PDF PubMed Google Scholar, 9.Streuli M. Krueger N.X. Thai T. Tang M. Saito H. EMBO J. 1990; 9: 2399-2407Crossref PubMed Scopus (270) Google Scholar). It lacks critical catalytic residues and cannot readily bind phosphotyrosine (10.Felberg J. Lefebvre D.C. Lam M. Wang Y. Ng D.H. Birkenhead D. Cross J.L. Johnson P. J. Biol. Chem. 2004; 279: 3455-3462Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). Two functions have been proposed for CD45-D2: 1) to interact with and stabilize the catalytic D1 domain of CD45 (7.Felberg J. Johnson P. J. Biol. Chem. 1998; 273: 17839-17845Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 11.Felberg J. Johnson P. Biochem. Biophys. Res. Comm. 2000; 271: 292-298Crossref PubMed Scopus (20) Google Scholar) and 2) to bind substrate and facilitate substrate recruitment (10.Felberg J. Lefebvre D.C. Lam M. Wang Y. Ng D.H. Birkenhead D. Cross J.L. Johnson P. J. Biol. Chem. 2004; 279: 3455-3462Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar, 12.Kashio N. Matsumoto W. Parker S. Rothstein D.M. J. Biol. Chem. 1998; 273: 33856-33863Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). CD45 is required for T cell activation by constitutively dephosphorylating the negative regulatory tyrosine of Lck, Tyr505 (reviewed in Refs. 4.Hermiston M.L. Xu Z. Weiss A. Annu. Rev. Immunol. 2003; 21: 107-137Crossref PubMed Scopus (667) Google Scholar and 13.Chan A.C. Shaw A.S. Curr. Opin. Immunol. 1996; 8: 394-401Crossref PubMed Scopus (170) Google Scholar, 14.Alexander D.R. Semin. Immunol. 2000; 12: 349-359Crossref PubMed Scopus (127) Google Scholar, 15.Johnson P. Felberg J. Mod. Asp. Immunobiol. 2000; 1: 156-159Google Scholar). The restoration of T cell signaling by activated Lck in CD45− T cells (16.Duplay P. Alcover A. Fargeas C. Sekaly R.P. Branton P.E. J. Biol. Chem. 1996; 271: 17896-17902Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar) and restoration of T cell development in the CD45 null mouse by expression of Lck Y505F (17.Seavitt J.R. White L.S. Murphy K.M. Loh D.Y. Perlmutter R.M. Thomas M.L. Mol. Cell. Biol. 1999; 19: 4200-4208Crossref PubMed Scopus (65) Google Scholar) support this finding. Dephosphorylation at Tyr505 creates a “primed” Lck molecule that can become activated upon TCR encounter with antigen, which initiates the signal transduction cascade by phosphorylating downstream substrates such as CD3ζ and ZAP-70 and leads to the activation of PLCγ-1, inositol 1,4,5-trisphosphate (IP3) generation, an increase in intracellular calcium, CD69 expression, and IL2 production (18.Mustelin T. Tasken K. Biochem. J. 2003; 371: 15-27Crossref PubMed Scopus (238) Google Scholar, 19.Mustelin T. Rahmouni S. Bottini N. Alonso A. Immunol. Rev. 2003; 191: 139-147Crossref PubMed Scopus (55) Google Scholar). However, in CD45−/- thymocytes and in some CD45− T cell lines, Lck is hyperphosphorylated at both the negative and autophosphorylation sites, suggesting that CD45 may also down-regulate Lck activity by dephosphorylating the autophosphorylation site (reviewed in Refs. 20.Ashwell J.D. D'Oro U. Immunol. Today. 1999; 20: 412-416Abstract Full Text Full Text PDF PubMed Scopus (83) Google Scholar and 21.Thomas M.L. Brown E.J. Immunol. Today. 1999; 20: 406-411Abstract Full Text Full Text PDF PubMed Scopus (161) Google Scholar). CD45 has also been implicated in down-regulating Src family kinase activity by negatively regulating integrin and CD44-mediated T cell adhesion (22.Shenoi H. Seavitt J. Zheleznyak A. Thomas M.L. Brown E.J. J. Immunol. 1999; 162: 7120-7127PubMed Google Scholar, 23.Li R.H. Wong N. Jabali M.D. Johnson P. J. Biol. Chem. 2001; 276: 28767-28773Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar). Although Lck and, to a lesser extent, Fyn are considered major substrates for CD45 in T cells (reviewed in Refs. 24.Chan A.C. Desai D.M. Weiss A. Annu. Rev. Immunol. 1994; 12: 555-592Crossref PubMed Scopus (500) Google Scholar and 25.Weil R. Veillette A. Curr. Top. Microbiol. Immunol. 1996; 205: 63-87PubMed Google Scholar), other CD45 substrates may also exist such as TCRζ, ZAP-70 and Jak kinases (26.Furukawa T. Itoh M. Krueger N.X. Streuli M. Saito H. Proc. Natl. Acad. Sci. U. S. A. 1994; 91: 10928-10932Crossref PubMed Scopus (150) Google Scholar, 27.Mustelin T. Williams S. Tailor P. Couture C. Zenner G. Burn P. Ashwell J.D. Altman A. Eur. J. Immunol. 1995; 25: 942-946Crossref PubMed Scopus (62) Google Scholar, 28.Irie-Sasaki J. Sasaki T. Matsumoto W. Opavsky A. Cheng M. Welstead G. Griffiths E. Krawczyk C. Richardson C.D. Aitken K. Iscove N. Koretzky G. Johnson P. Liu P. Rothstein D.M. Penninger J.M. Nature. 2001; 409: 349-354Crossref PubMed Scopus (458) Google Scholar). Although CD45-D2 has no catalytic activity, it has been implicated in regulating TCR signaling. CD45, but not a CD45-LAR-D2 chimera, decreased CD3ζ phosphorylation levels and induced ZAP-70 phosphorylation and IL2 production upon TCR stimulation, suggesting that CD45-D2 was important for directing CD3ζ dephosphorylation and ZAP-70 phosphorylation (12.Kashio N. Matsumoto W. Parker S. Rothstein D.M. J. Biol. Chem. 1998; 273: 33856-33863Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). Mutation of residues within the unique acidic 19 amino acid insert in CD45-D2 resulted in increased calcium levels in one T cell line and sustained calcium influx after TCR stimulation in another cell line (29.Wang Y. Liang L.Z. Esselman W.J. J. Immunol. 2000; 164: 2557-2564Crossref PubMed Scopus (15) Google Scholar). However, in another study, calcium levels and MAPK activation were reduced when cells expressing the 19 amino acid deletion mutant were stimulated via the TCR (30.Greer S.F. Wang Y. Raman C. Justement L.B. J. Immunol. 2001; 166: 7208-7218Crossref PubMed Scopus (21) Google Scholar). CD45 can associate with Lck in T cells (31.Schraven B. Kirchgessner H. Gaber B. Samstag Y. Meuer S. Eur. J. Immunol. 1991; 21: 2469-2477Crossref PubMed Scopus (91) Google Scholar, 32.Koretzky M. S. J. Biol. Chem. 1993; Full Text PDF PubMed Google Scholar), and in indicate that is a both the catalytic and non-catalytic of Lck and CD45 D.C. Felberg J. Cross J.L. Johnson P. Biophys. 2003; PubMed Scopus Google Scholar). CD45-D2 to the kinase domain of Lck in a and the in Lck for this the of Lck, is implicated in substrate and dephosphorylation (10.Felberg J. Lefebvre D.C. Lam M. Wang Y. Ng D.H. Birkenhead D. Cross J.L. Johnson P. J. Biol. Chem. 2004; 279: 3455-3462Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). to the the domains of CD45 and Lck in T cells. and human Jurkat leukemia T cell lines, clone E6.1 (CD45 and clone 45.01 (CD45 were and in with and and cell were by with full-length mouse CD45RABC, mouse lacking residues or the H. A. J. 1990; PubMed Scopus Google Scholar) as a of residues the catalytic D1 and PTP domain and the (7.Felberg J. Johnson P. J. Biol. Chem. 1998; 273: 17839-17845Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar). CD45RABC-D2 the extracellular RABC isoform, the transmembrane region, the region, the inactive second PTP domain, and carboxyl and were active and mouse CD45 expression was by of the for and expression of mouse CD45, two and cells were for further and and and monoclonal and were I. S. Trowbridge I.S. J. PubMed Scopus Google Scholar). TCR and CD45, were were protein or to and domain were as D.H.W. Jabali M.D. Maiti A. P. K. T. B. Johnson P. Biochem. J. PubMed Scopus (15) Google Scholar). MAPK, was to horseradish or fluorescein was with or was and CD69 was was and monoclonal was were for with of CD45 CD45 and and with of or cells were with of a of cells were a and and were in or with and were for and at for at were by with of for at CD45 was cells in of with of or cells in with of for Lck Lck was cells in of and with of protein with to were with The were in of for and at for were by and to polyvinylidene membrane was by with containing mAb, and mouse and human CD45 were by domain and Lck was with with the of the phosphorylation state of Lck, was used with protein were and to In Lck were and with of was in to TCR as L.B. J. J. M. J. Immunol. 1990; Google Scholar). cells in of containing were with the at a of and at for of containing and was and the cells were at for another The cells were with containing and and in at a of a line was the was was to and was was used as a to that cells to the influx of cell was used to the and were by a by and to and of the were and IL2 in of containing were stimulated in with IL2 was after 12 by in or of tyrosine and MAPK cells were stimulated with to at were with and were and of were at for at The was with and cell were and to The were with or and with and of CD69 expression after TCR stimulation, cells were in of and stimulated with at for or to of was and cells were at to were with and by Expression of CD45RABC-D2 in CD45− Jurkat T TCR CD45-D2 has functions that are of the catalytic domain, a construct expressing full-length mouse lacking the catalytic D1 domain was CD45− Jurkat T cells for were for expression of mouse CD45 and, also to levels of expression the cells, and the CD45RABC-D2 cells. cells were and at two were for and and was also CD45− Jurkat T cells. The levels of expression of mouse CD45, TCR, and were by to levels of expression In the of human CD45 was by as levels of human CD45 been in the cells J. T. Weiss A. Proc. Natl. Acad. Sci. U. S. A. 1991; PubMed Scopus Google Scholar) and were in this case the expression of CD45RABC-D2 and in cells after of mouse CD45, to and with an In the CD45− Jurkat cells, Lck is hyperphosphorylated at the negative regulatory site and TCR stimulation not (reviewed in Refs. 1.Thomas M.L. Annu. Rev. Immunol. 1989; 7: 339-369Crossref PubMed Google Scholar, 2.Trowbridge I.S. Thomas M.L. Annu. Rev. Immunol. 1994; 12: 85-116Crossref PubMed Scopus (666) Google Scholar, and 4.Hermiston M.L. Xu Z. Weiss A. Annu. Rev. Immunol. 2003; 21: 107-137Crossref PubMed Scopus (667) Google Scholar). of the full-length CD45RABC, but not CD45RABC-D2, the induction of tyrosine phosphorylation upon TCR stimulation also the induction of expression of CD69 to the expression of CD45RABC-D2 no CD69 expression, when stimulation was to not This is with CD45RABC-D2 lacking protein tyrosine phosphatase activity. CD45RABC-D2 with Lck in CD45− and CD45+ Jurkat T and in Lck in the CD45+ Jurkat T CD45RABC-D2 was CD45+ Jurkat T cells and cells were for levels of expression of CD45RABC-D2 and levels of expression of human CD45, TCR, and with the levels of the line indicates the expression of expression of mouse CD45RABC-D2 was also by for in cell were also with domain that both mouse and human CD45. Felberg and P. This the of human CD45 in cells and cells with and both human and mouse CD45RABC-D2 in and cells The primarily two CD45 in and cells that to the of CD45 H. T. Rothstein D.M. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar). the CD45RABC-D2 lacking D1 but expressing to a as the of CD45. CD45 was of CD45+ and CD45− cells, to and for and that Lck with and CD45RABC-D2 in both the CD45+ and CD45− T cells. This that CD45RABC-D2 can associate with Lck in the of CD45. It also suggests that the of Lck Lck is hyperphosphorylated in CD45− but not in the CD45+ cells In this that the association can in the of the active PTP domain, Lck was and by The tyrosine phosphorylation state of Lck was by with an mAb, increased Lck phosphorylation in the Jurkat cells expressing of Lck phosphorylation in CD45+ and CD45− with that in cells that the phosphorylation was the in the CD45+ cells but that in the CD45− Jurkat cells. In the of Lck phosphorylation was by the of CD45RABC-D2 expression Lck was not This finding suggests that the of CD45RABC-D2 is Lck dephosphorylation in CD45+ Jurkat T cells. CD45RABC-D2 MAPK or CD69 the of CD45RABC-D2 TCR signaling and T cell the cells were stimulated with TCR expressing CD45RABC-D2 a induction of phosphorylation was in the CD45+ cells after phosphorylation was not in the cells To this to in downstream MAPK phosphorylation and CD69 expression levels were that, MAPK phosphorylation was in the CD45− T cells and induced at in the CD45+ T cells, the of CD45RABC-D2 did not significantly the induction or of CD69 expression is downstream of MAPK activation R. D. R. A. Immunol. Today. 1994; Full Text PDF PubMed Scopus Google Scholar), the induction of CD69 expression after TCR stimulation. that the of CD69 was decreased in cells. There was also a of CD69 induction at but by CD69 induction was This suggests that the in the induction of tyrosine phosphorylation is to downstream in the MAPK to CD69 CD45RABC-D2 and IL2 CD45RABC-D2 the other major signaling in TCR signaling, the calcium pathway, cells were with the in intracellular calcium levels were the and after a line been TCR was to the cells. that, although the CD45+ cells a increase in intracellular calcium, cells expressing CD45RABC-D2 no calcium was to Jurkat cells expressing no CD45 The addition of to in intracellular calcium, that of the cells were of to TCR signaling in Jurkat T cells to IL2 To the of TCR signaling in the CD45+ T cells, cells were stimulated with TCR with The of IL2 after 12 of stimulation was by that the expression of CD45RABC-D2 reduced IL2 production in CD45+ Jurkat cells. was also when the and were used for stimulation not IL2 was not in the of CD45 or by cells did not levels of after of stimulation not This indicates that a CD45 protein lacking the catalytic domain of CD45 can associate with Lck in T cells, of the phosphorylation state of Although the of CD45 this was not in data indicate that the second PTP domain of CD45, can bind to Lck in a (10.Felberg J. Lefebvre D.C. Lam M. Wang Y. Ng D.H. Birkenhead D. Cross J.L. Johnson P. J. Biol. Chem. 2004; 279: 3455-3462Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). data this that expression of CD45RABC-D2 in an increase in Lck phosphorylation in CD45+ T cells, suggesting that, in the of an active CD45RABC-D2 to Lck and its dephosphorylation by CD45. This is also with in data a for D2 in substrate and substrate dephosphorylation (10.Felberg J. Lefebvre D.C. Lam M. Wang Y. Ng D.H. Birkenhead D. Cross J.L. Johnson P. J. Biol. Chem. 2004; 279: 3455-3462Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar). In when CD45 D2 was with and the was expressed in T cells, was no in CD3ζ (12.Kashio N. Matsumoto W. Parker S. Rothstein D.M. J. Biol. Chem. 1998; 273: 33856-33863Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar) to that CD45-D2 has a in The data are with this as that CD45RABC-D2 to the major CD45 substrate in T cells, However, it is also that other of CD45 may facilitate an with the extracellular domain of CD45, primarily has been to associate with which in Lck S. Z. J. P. A. S. N. P. J. D.R. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, D. D. K. J. 1996; PubMed Scopus Google Scholar). Although the transmembrane of CD45 is not required for its association with Lck, it an with K. Maiti A. Ng D.H.W. Johnson P. A. J. Biol. Chem. 1995; Full Text Full Text PDF PubMed Scopus Google Scholar), which also to Lck A. D. S. D. J. Biol. Chem. 1999; Full Text Full Text PDF PubMed Scopus Google Scholar). Although CD45RABC-D2 can associate with Lck in the of CD45, CD45RABC-D2 may also bind to CD45 a with CD45 not This may also to the reduced of CD45, as it has been that the of one CD45 molecule may bind the catalytic domain of another and down-regulate its function D.M. J. J. Weiss A. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar, R. Xu Z. J.L. N. Weiss A. Cell. 2000; Full Text Full Text PDF PubMed Scopus Google Scholar). In Jurkat T cells, CD45 is required for the TCR signaling the induction of tyrosine production of IP3, and increase in intracellular calcium levels J. T. Weiss A. Proc. Natl. Acad. Sci. U. S. A. 1991; PubMed Scopus Google Scholar, T. Weiss A. J. Immunol. 1992; Google Scholar). This TCR signaling has been attributed to the of CD45 to the negative regulatory in Lck, which a Lck that can activated when the TCR antigen (reviewed in Refs. 4.Hermiston M.L. Xu Z. Weiss A. Annu. Rev. Immunol. 2003; 21: 107-137Crossref PubMed Scopus (667) Google Scholar, 15.Johnson P. Felberg J. Mod. Asp. Immunobiol. 2000; 1: 156-159Google Scholar, and T. Tasken K. Biochem. J. 2003; 371: 15-27Crossref PubMed Scopus (238) Google Scholar). In this study, CD45RABC-D2 the of CD45 to Lck and resulted in TCR signaling. It a in the induction of but did not the tyrosine phosphorylation of MAPK or the induction of CD69 However, it did have a calcium and IL2 In other deletion or of the unique acidic in CD45-D2 in calcium signaling and, in one MAPK activation in T cells (29.Wang Y. Liang L.Z. Esselman W.J. J. Immunol. 2000; 164: 2557-2564Crossref PubMed Scopus (15) Google Scholar, S.F. Wang Y. Raman C. Justement L.B. J. Immunol. 2001; 166: 7208-7218Crossref PubMed Scopus (21) Google Scholar) and when CD45-D2 was with TCR-induced IL2 production was reduced (12.Kashio N. Matsumoto W. Parker S. Rothstein D.M. J. Biol. Chem. 1998; 273: 33856-33863Abstract Full Text Full Text PDF PubMed Scopus (51) Google Scholar). data a for the D2 domain in regulating TCR signaling. Jurkat T cells and its associated T cell signaling have been in the of the TCR signaling Weiss A. Rev. Immunol. 2004; PubMed Scopus Google Scholar). However, one to the of the Jurkat T cell line is that it is in the expression of two and that in the activation of the However, this TCR signaling in this and other is not as the of in TCR signaling is understood. TCR signaling at two major signaling to IL2 the and the calcium pathway, and CD45 and Lck were to required for both CD45 is required for the activation and induction of tyrosine phosphorylation of J. T. Weiss A. Proc. Natl. Acad. Sci. U. S. A. 1991; PubMed Scopus Google Scholar, T. Weiss A. J. Immunol. 1992; Google Scholar), which and IP3, and the of calcium intracellular (reviewed in Annu. Rev. Immunol. 2001; 19: PubMed Scopus Google Scholar). In TCR-induced phosphorylation of MAPK was Src family kinase activation as a Src family kinase its phosphorylation not that CD45RABC-D2 severely the calcium signal but not the MAPK pathway, suggesting that the calcium may have a for activation the MAPK and may to in Lck activity. the activation of the MAPK can at two 1) via PLCγ-1, and activation C. J. M. Ostergaard H.L. 2000; PubMed Google Scholar) and 2) by a that to which is to upon TCR stimulation (reviewed in Refs. W. Semin. Immunol. 2000; 12: PubMed Scopus Google Scholar and Immunol. Rev. 2003; PubMed Scopus Google Scholar), and by reduced Lck activity. is that may its of CD45RABC-D2 is the calcium is not activity were reduced in CD45RABC-D2 expressing cells, one a in the to MAPK activation as well as a in calcium signaling. However, was no this is to activated upon TCR stimulation in Jurkat T cells C. J. M. Ostergaard H.L. 2000; PubMed Google Scholar, D. T. Weiss A. 1998; PubMed Scopus Google Scholar). with this the expression of CD45RABC-D2 the TCR-induced phosphorylation of not This suggests that the in the calcium signal may downstream of The by CD45RABC-D2 to but are the which is by the Src family or T cell calcium the of which is understood. the expression of CD45RABC-D2 the production of IL2 in to TCR stimulation. This was via a major the calcium pathway, not the calcium but not MAPK signaling, upon TCR are associated with the induction of in T cells R.H. Annu. Rev. Immunol. 2003; 21: PubMed Scopus Google Scholar). This suggests that this type of signaling upon TCR CD45 was dephosphorylating Lck or Lck phosphorylation Trowbridge for the of and Johnson at the for the cells and with the calcium and Cross for the

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