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• W2079461939 abstract "T lymphocyte activation through stimulation of the T cell receptor complex and co-stimulatory receptors is associated with acute tyrosine phosphorylation of intracellular proteins, which in turn mediate downstream signaling events that regulate interleukin-2 expression and cell proliferation. The extent of protein tyrosine phosphorylation is rapidly attenuated after only 1–2 min of stimulation as a means of tightly controlling the initial signaling response. Here we show that this attenuation of tyrosine phosphorylation of Shc, CrkL, and the proto-oncogene Cbl is mimicked by treatment of mouse T lymphocytes or cultured Jurkat cells with phorbol 12-myristate 13-acetate. This effect is blocked by the specific protein kinase C inhibitor GF109203X, but not by PD98059, an inhibitor of MEK1/2 kinase. Activation of protein kinase C by phorbol ester also causes rapid (t 12 = 2 min) dissociation of both CrkL and p85/phosphoinositide 3-kinase from Cbl concomitant with Cbl tyrosine dephosphorylation. More important, GF109203X treatment of Jurkat cells prior to T cell receptor stimulation by anti-CD3/CD4 antibodies results in an enhanced (2-fold) peak of Cbl phosphorylation compared with that observed in control cells. Furthermore, the rate of attenuation of both Cbl tyrosine phosphorylation and its association with CrkL following stimulation with anti-CD3/CD4 antibodies is much slower in Jurkat cells treated with GF109203X. Taken together, these data provide strong evidence that one or more isoforms of phorbol ester-responsive protein kinase C play a key role in a feedback mechanism that attenuates tyrosine phosphorylation of proteins and reverses formation of signaling complexes in response to T cell receptor activation. T lymphocyte activation through stimulation of the T cell receptor complex and co-stimulatory receptors is associated with acute tyrosine phosphorylation of intracellular proteins, which in turn mediate downstream signaling events that regulate interleukin-2 expression and cell proliferation. The extent of protein tyrosine phosphorylation is rapidly attenuated after only 1–2 min of stimulation as a means of tightly controlling the initial signaling response. Here we show that this attenuation of tyrosine phosphorylation of Shc, CrkL, and the proto-oncogene Cbl is mimicked by treatment of mouse T lymphocytes or cultured Jurkat cells with phorbol 12-myristate 13-acetate. This effect is blocked by the specific protein kinase C inhibitor GF109203X, but not by PD98059, an inhibitor of MEK1/2 kinase. Activation of protein kinase C by phorbol ester also causes rapid (t 12 = 2 min) dissociation of both CrkL and p85/phosphoinositide 3-kinase from Cbl concomitant with Cbl tyrosine dephosphorylation. More important, GF109203X treatment of Jurkat cells prior to T cell receptor stimulation by anti-CD3/CD4 antibodies results in an enhanced (2-fold) peak of Cbl phosphorylation compared with that observed in control cells. Furthermore, the rate of attenuation of both Cbl tyrosine phosphorylation and its association with CrkL following stimulation with anti-CD3/CD4 antibodies is much slower in Jurkat cells treated with GF109203X. Taken together, these data provide strong evidence that one or more isoforms of phorbol ester-responsive protein kinase C play a key role in a feedback mechanism that attenuates tyrosine phosphorylation of proteins and reverses formation of signaling complexes in response to T cell receptor activation. T cell receptor (TCR) 1The abbreviations TCRT cell receptorPIphosphoinositideIRS-1insulin receptor substrate 1PMAphorbol 12-myristate 13-acetateMAPKmitogen-activated protein kinasePAGEpolyacrylamide gel electrophoresisMEKMAPK/extracellular receptor kinase kinase 1The abbreviations TCRT cell receptorPIphosphoinositideIRS-1insulin receptor substrate 1PMAphorbol 12-myristate 13-acetateMAPKmitogen-activated protein kinasePAGEpolyacrylamide gel electrophoresisMEKMAPK/extracellular receptor kinase kinaseligation by antigen-presenting cells or by antibodies to the CD3-TCR complex causes rapid increases in the activities of protein-tyrosine kinases and in the tyrosine phosphorylation of cellular substrates. The kinases involved belong to two families of nonreceptor protein-tyrosine kinases, the Src (Fyn and Lck) and Syk (Syk and ZAP-70) families (1Alberola-Ila J. Takaki S. Kerner J.D. Perlmutter R.M. Annu. Rev. Immunol. 1997; 15: 125-154Crossref PubMed Scopus (230) Google Scholar, 2Cantrell D.A. Annu. Rev. Immunol. 1996; 14: 259-274Crossref PubMed Scopus (592) Google Scholar, 3Wange R.L. Samelson L.E. Immunity. 1996; 5: 197-205Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar). Activation of Lck and/or Fyn leads to the tyrosine phosphorylation of immunoreceptor tyrosine-based activation motifs present in the intracellular segments of the CD3 ε- and ζ-proteins (4Reth M. Nature. 1989; 338: 383-384Crossref PubMed Scopus (1154) Google Scholar, 5Samelson L.E. Klausner R.D. J. Biol. Chem. 1992; 267: 24913-24916Abstract Full Text PDF PubMed Google Scholar), followed by the recruitment, tyrosine phosphorylation, and activation of ZAP-70. This biochemical response couples the TCR to a diverse group of signal transduction molecules, including adaptor proteins, serine/threonine kinases, phospholipids and their cleavage products, and GTP-binding proteins, leading ultimately to interleukin-2 production and cell proliferation. Such proliferation of T lymphocytes directed against a specific antigen is crucial to mounting appropriate cell-based immune responses to foreign entities.The increased tyrosine phosphorylation of cellular proteins observed after TCR activation is a transient process, apparently a result of the combined actions of protein-tyrosine kinases and phosphatases. The ensuing desensitization of tyrosine kinase signaling after stimulation is likely to be important in coordinating the complex network of events that lead to T cell proliferation. An integral part of this response is an internalization of the TCR complex, followed by its degradation by a mechanism that involves the targeting of the internalized receptors to an endocytic degradative pathway (6Reinherz E. Meuer S. Fitzgerald K. Hussey R. Levine H. Schlossman S. Cell. 1982; 30: 735-743Abstract Full Text PDF PubMed Scopus (365) Google Scholar, 7Valitutti S. Muller S. Cella M. Padovan E. Lanzavecchia A. Nature. 1995; 375: 148-151Crossref PubMed Scopus (984) Google Scholar). However, the maximal level of protein tyrosine phosphorylation in response to TCR stimulation occurs after only 1 or 2 min, and the decrease in tyrosine phosphorylation of cell proteins is rapid following this peak (8Weiss A. Littman D.R. Cell. 1994; 76: 263-274Abstract Full Text PDF PubMed Scopus (1943) Google Scholar). The rapid kinetics of protein tyrosine dephosphorylation indicate that T cell receptor internalization cannot fully account for deactivation of the signaling pathways following T cell stimulation, but other mechanisms that may be involved are unknown.Two cellular protein substrates for T cell receptor-activated tyrosine kinases that undergo rapid phosphorylation and dephosphorylation in response to antigen presentation are the proto-oncogene products c-Cbl and CrkL. Both have prominent roles in T cell signaling, serving to link receptor tyrosine kinases to downstream effectors such as p85/PI 3-kinase (9Meisner H. Conway B.R. Hartley D. Czech M.P. Mol. Cell. Biol. 1995; 15: 3571-3578Crossref PubMed Scopus (212) Google Scholar, 10Fukazawa 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, 11Liu Y.-C. Altman A. Cell. Signaling. 1998; 10: 377-385Crossref PubMed Scopus (84) Google Scholar). CrkL, the cellular homologue of the v-crkoncogene product (12Mayer B.J. Hamaguchi M. Hanafusa H. Nature. 1988; 332: 272-275Crossref PubMed Scopus (516) Google Scholar), consists of one SH2 and two C-terminal SH3 domains (13Matsuda M. Tanaka S. Nagata S. Kojima A. Kurata T. Shibuya M. Mol. Cell. Biol. 1992; 12: 3482-3489Crossref PubMed Scopus (245) Google Scholar, 14ten Hoeve J. Morris C. Heisterkamp H. Groffen J. Oncogene. 1993; 8: 2469-2474PubMed Google Scholar). The SH3 domain of CrkL binds to several proteins, including C3G, Sos, and c-Abl (15Matsuda M. Hashimoto Y. Muroya K. Hasegawa H. Kurata T. Tanaka S. Nakamura S. Hattori S. Mol. Cell. Biol. 1994; 14: 5495-5500Crossref PubMed Scopus (183) Google Scholar, 16Feller S.M. Knudsen B. Hanafusa H. EMBO J. 1994; 13: 2341-2351Crossref PubMed Scopus (326) Google Scholar). Cbl is the cellular homologue of v-Cbl, an oncogene that causes lymphomas in murine B cells (17Langdon W.Y. Hartley J. Klinken S. Ruscetti S. Morse H. Proc. Natl. Acad. Sci. U. S. A. 1989; 86: 1168-1172Crossref PubMed Scopus (281) Google Scholar, 18Blake T.J. Shapiro M. Morse H.C. Langdon W.Y. Oncogene. 1991; 6: 653-657PubMed Google Scholar). Cbl contains an amino-terminal phosphotyrosine-binding domain (19Lupher Jr., M.L. Reedquist K.A. Miyake S. Langdon W.Y. Band H. J. Biol. Chem. 1996; 271: 24063-24068Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar), a Ring finger domain, and a carboxyl-terminal leucine zipper domain. Cbl also possesses a number of proline-rich motifs as well as several tyrosine residues in the C terminus that serve as binding sites for SH3 and SH2 domains, respectively (18Blake T.J. Shapiro M. Morse H.C. Langdon W.Y. Oncogene. 1991; 6: 653-657PubMed Google Scholar). In T lymphocytes, TCR ligation results in the association of a large pool of CrkL and Cbl through either the SH2 or SH3 domain of CrkL or both (20De Jong R. ten Hoeve J. Heisterkamp N. Groffen J. J. Biol. Chem. 1995; 270: 21468-21471Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar, 21Buday L. Khwaja A. Sipeki S. Faragó A. Downward J. J. Biol. Chem. 1996; 271: 6159-6163Abstract Full Text Full Text PDF PubMed Scopus (133) Google Scholar, 22Reedquist K. Fukazawa T. Panchamoorthy G. Langdon W.Y. Shoelson S.E. Druker B.J. Band H. J. Biol. Chem. 1996; 271: 8435-8442Abstract Full Text Full Text PDF PubMed Scopus (162) Google Scholar, 23Sattler M. Salgia R. Shrikhande G. Verma S. Pisick E. Prasad K.V.S. Griffin J.D. J. Biol. Chem. 1997; 272: 10248-10253Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar, 24Barber D.L. Mason J.M. Fukazawa T. Reedquist K.A Druker B.J. Band H. D'Andrea A.D. Blood. 1997; 89: 3166-3174Crossref PubMed Google Scholar).Genetic and biochemical studies have generally supported the concept that Cbl functions as a negative regulator of receptor tyrosine kinase signaling (25Yoon C.H. Lee J. Jongeward G.D. Sternberg P.W. Science. 1995; 269: 1102-1105Crossref PubMed Scopus (281) Google Scholar, 26Meisner H. Daga A. Buxton J. Fernández B. Chawla A. Banerjee U. Czech M.P. Mol. Cell. Biol. 1997; 17: 2217-2225Crossref PubMed Scopus (118) Google Scholar, 27Ota Y. Samelson L.E. Science. 1997; 276: 418-420Crossref PubMed Scopus (225) Google Scholar, 28Ueno H. Sasaki S. Miyagawa K. Honda H. Mitani K. Yazaki Y. Hirai H. J. Biol. Chem. 1997; 272: 8739-8743Abstract Full Text Full Text PDF PubMed Scopus (70) Google Scholar). Overexpression of c-Cbl in mast cells suppresses Syk kinase activity (27Ota Y. Samelson L.E. Science. 1997; 276: 418-420Crossref PubMed Scopus (225) Google Scholar) and impairs Ras-dependent AP1 activation after TCR ligation in Jurkat cells (29Rellaham B.L. Garham L.J. Stoica B. DeBell K.E. Bonvini E. J. Biol. Chem. 1997; 272: 30806-30811Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). We reported that D-Cbl, the Drosophila homologue of Cbl containing only the N-terminal portion of the protein, acts as a negative regulator of receptor tyrosine kinase-mediated R7 photoreceptor cell development inDrosophila (26Meisner H. Daga A. Buxton J. Fernández B. Chawla A. Banerjee U. Czech M.P. Mol. Cell. Biol. 1997; 17: 2217-2225Crossref PubMed Scopus (118) Google Scholar). The use of c-Cbl-deficient mice has provided further evidence that c-Cbl is involved in the negative control of T cell function. The c-Cbl-deficient mice display marked changes in their hemopoietic profiles, including an enhanced selection of CD4+ T cells, altered TCR expression, lymphoid hyperplasia, primary splenic extramedullary hemopoiesis, and increased ZAP-70 activity (30Murphy M.A. Schnall R.G. Venter D.J. Barnett L. Bertoncello I. Thien C.B.F. Langdon W.Y. Bowtell D.V.L. Mol. Cell. Biol. 1998; 18: 4872-4882Crossref PubMed Scopus (331) Google Scholar, 31Naramura M. Kole H.K. Hu R.J. Gu H. Proc. Natl. Acad. Sci. U. S. A. 1998; 95: 15547-15552Crossref PubMed Scopus (288) Google Scholar). Interestingly, the tyrosine phosphorylation of Cbl and its association with p85/p110 PI 3-kinase indicate that the protein also plays some positive signaling role in T cell function. This is reinforced by recent experiments on interleukin-4 signaling (32Ueno H. Sasaki K. Honda H. Nakamoto T. Yamagata T. Miyagawa K. Mitani K. Yazaki Y. Hirai H. Blood. 1998; 91: 46-53Crossref PubMed Google Scholar) and the fact that T cell activation is wortmannin-sensitive (33Shi J. Cinek T. Truitt K.E. Imboden J.B. J. Immunol. 1997; 158: 4688-4695PubMed Google Scholar).One possible mechanism for the attenuation of tyrosine-phosphorylated receptors and substrate proteins that occurs following initial tyrosine phosphorylation in response to TCR stimulation is suggested by recent data on the serine/threonine phosphorylation of these proteins. For example, substantial evidence suggests that rapid serine/threonine phosphorylation of the insulin receptor and its substrate IRS-1 correlates with their decreased tyrosine phosphorylation and decreased binding of IRS-1 to p85/p110 PI 3-kinase (34De Fea K. Roth R.A. Biochemistry. 1997; 36: 181-189Crossref PubMed Scopus (222) Google Scholar, 35De Fea K. Roth R.A. J. Biol. Chem. 1997; 272: 31400-31406Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar). The serine/threonine phosphorylation of IRS-1 causes its binding to 14-3-3 proteins, which may block further tyrosine phosphorylation (36Kosaki A. Yamada K. Suga J. Otaka A. Kuzuya H. J. Biol. Chem. 1998; 273: 940-944Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar). It has been shown recently that after TCR stimulation, Cbl is phosphorylated not only on tyrosine, but also on serine, and that this post-translational modification regulates its interaction with 14-3-3 ζ-proteins (37Liu Y.-C. Elly C. Yoshida H. Bonnefoy-Berard N. Altman A. J. Biol. Chem. 1996; 271: 14591-14595Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar,38Liu Y.-C. Liu Y. Elly C. Yoshida H. Lipkowitz S. Altman A. J. Biol. Chem. 1997; 272: 9979-9985Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). The phorbol ester PMA was also able to cause serine phosphorylation of Cbl and to induce its interaction with 14-3-3 ζ-proteins, implicating the protein kinase C family of serine/threonine kinases in Cbl function. These considerations prompted us to test whether protein kinase C isoforms might be involved in mediating the attenuation of Cbl tyrosine phosphorylation in T lymphocytes following T cell receptor activation. We show here that activation of protein kinase C by phorbol ester causes rapid dephosphorylation of tyrosine phosphate sites on three protein substrates of T cell tyrosine kinases (Shc, CrkL, and Cbl) and that the protein kinase C inhibitor GF109203X causes hyperphosphorylation of Cbl in response to T cell receptor engagement. These results support a key role of protein kinase C in signal attenuation during T lymphocyte stimulation.DISCUSSIONThe data presented here show that PMA addition to T cells causes a rapid decline in the tyrosine phosphorylation state of Shc, CrkL, and Cbl (Fig. 1). This effect coincides with rapid dissociation of Cbl-CrkL protein complexes (Fig. 2). More important, the time course of this dissociation is similar to that observed following the transient formation of Cbl-CrkL complexes in response to TCR/CD3 receptor stimulation (Fig. 6). Conversely, when protein kinase C activity is blocked by the inhibitor GF109203X, tyrosine phosphorylation of Cbl and CrkL following TCR/CD3 ligation is significantly amplified (Fig. 5). These results suggest that activation of protein kinase C following TCR ligation, thought to initiate downstream signaling events, also leads to a feedback mechanism that reduces tyrosine phosphorylation of Cbl and CrkL and hence return to the non-activated state. The PMA-induced dephosphorylation of Shc and other proteins (Fig. 1) and its prevention by GF109203X indicate that protein kinase C activation modulates the tyrosine phosphorylation state of other cellular proteins besides Cbl and CrkL.It is well established that both phorbol esters and TCR ligation by antigen-presenting cells or by anti-CD3 antibody induce internalization of the TCR. The half-life of the TCR complex on the cell surface after PMA treatment is ∼10 min (58Cantrell D.A. Davies A.A Crumpton M.J. Proc. Natl. Acad. Sci. U. S. A. 1985; 82: 8158-8162Crossref PubMed Scopus (214) Google Scholar, 59Lauritsen J.P. Christensen M.D. Dietrich J. Kastrup J. Odum N. Geisler C. J. Immunol. 1998; 161: 260-267PubMed Google Scholar, 60Dietrich J. Backstrom T. Lauritsen J.P.H. Kastrup J. Christensen M.D. von Bülow F. Palmer E. Geisler C. J. Biol. Chem. 1998; 273: 24232-24238Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar). The TCR is not degraded, but is recycled in a functional state back to the cell membrane (61Minami Y. Samelson L.E. Klausner R.D. J. Biol. Chem. 1987; 262: 13342-13347Abstract Full Text PDF PubMed Google Scholar, 62Ruegg C.L. Rajasekar S. Stein B.S. Engleman E.G. J. Biol. Chem. 1992; 267: 18837-18843Abstract Full Text PDF PubMed Google Scholar). In contrast to PMA-induced down-regulation and recycling, TCR ligation by antigen-presenting cells or anti-CD3 antibody results in an internalization and targeting to lysosomes for degradation (63Luton F. Buferne M. Davoust J. Schmitt-Verhulst A.M. Boyer C. J. Immunol. 1994; 153: 63-72PubMed Google Scholar, 64Valitutti S. Muller S. Salio M. Lanzavecchia A. J. Exp. Med. 1997; 185: 1859-1864Crossref PubMed Scopus (260) Google Scholar). The t 12 of ligand-induced TCR degradation has been shown by various investigators to be 15–30 min (6Reinherz E. Meuer S. Fitzgerald K. Hussey R. Levine H. Schlossman S. Cell. 1982; 30: 735-743Abstract Full Text PDF PubMed Scopus (365) Google Scholar, 7Valitutti S. Muller S. Cella M. Padovan E. Lanzavecchia A. Nature. 1995; 375: 148-151Crossref PubMed Scopus (984) Google Scholar, 63Luton F. Buferne M. Davoust J. Schmitt-Verhulst A.M. Boyer C. J. Immunol. 1994; 153: 63-72PubMed Google Scholar, 64Valitutti S. Muller S. Salio M. Lanzavecchia A. J. Exp. Med. 1997; 185: 1859-1864Crossref PubMed Scopus (260) Google Scholar, 65Luton F. Legendre V. Gorvel J.P. Schmitt-Verhulst A.M. Boyer C. J. Immunol. 1997; 158: 3140-3147PubMed Google Scholar, 66Telerman A. Amson R. Romasco F. Wybran J. Galand P. Mosselmans R. J. Immunol. 1987; 17: 991-997Google Scholar). By contrast, the data presented here show that the Cbl-CrkL complex is dissociated by PMA or OKT3 plus OKT4 (Figs. 1 and 6) significantly faster, with a t 12 of 2 min. Therefore, the dissociation of CrkL and Cbl precedes, and is not simply a consequence of, activation-induced TCR endocytosis. The similar kinetics of Cbl-CrkL dissociation by TCR ligation or by PMA and blockade of this dissociation by GF109203X are evidence that protein kinase C activation is involved.We also report here that PMA causes the dissociation of CrkL from the p85 subunit of PI 3-kinase (Fig. 2) and that Cbl mediates the association of p85 with CrkL (Fig. 3). These findings are consistent with results obtained in c-Fms Chinese hamster ovary cells activated by colony-stimulating factor-1, in which prior removal of Cbl from cell lysates diminished by 95% the amount of PI 3-kinase associated with CrkII (67Husson H. Mogarbi B. Schmid-Antomarchi H. Fischer S. Rossi B. Oncogene. 1997; 14: 2331-2338Crossref PubMed Scopus (32) Google Scholar). By contrast, in MO7e cells, CrkL appears to bind directly to p85 through the CrkL SH3 domains, and this interaction is further increased by Steel factor (23Sattler M. Salgia R. Shrikhande G. Verma S. Pisick E. Prasad K.V.S. Griffin J.D. J. Biol. Chem. 1997; 272: 10248-10253Abstract Full Text Full Text PDF PubMed Scopus (96) Google Scholar). The reason for these discrepancies is unknown and can reflect differences in the mechanisms of Cbl-CrkL association in different cell types. Although CrkL becomes tyrosine-phosphorylated upon T cell activation, no consensus motif is present for the binding of the SH2 domain of p85 (49Gesbert F. Garbay C. Bertoglio J. J. Biol. Chem. 1998; 273: 3986-3993Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar). These data suggest that Cbl may play a role as a multifunctional adaptor protein, interacting independently with CrkL and p85, and that PI 3-kinase is dissociated from Cbl after PMA stimulation. It is not known if p85 becomes serine-phosphorylated under the conditions described here; however, it has been demonstrated that serine phosphorylation of the p85 subunit of PI 3-kinase greatly reduces PI 3-kinase activity (68Dhand R. Hiles I. Panayotou G. Roche S. Fry M.J. Gout I. Totty N.F. Truong O. Vicendo P. Yonezawa K. Kasuga M. Courtneidge S.A. Waterfield M.D. EMBO J. 1994; 13: 522-533Crossref PubMed Scopus (414) Google Scholar,69Carpenter C. Auger K. Duckworth B. Hou W. Schaffhausen B. Cantley L.C. Mol. Cell. Biol. 1993; 13: 1657-1665Crossref PubMed Scopus (193) Google Scholar).The ability of the highly specific cell-permeable protein kinase C inhibitor GF109203X to block Cbl-CrkL dissociation is strong evidence that the activation of a conventional or novel protein kinase C isoform is required. GF109203X has no effect on the activity of receptor tyrosine kinases such as insulin, epidermal growth factor, and platelet-derived growth factor receptors (53Toullec D. Pianetti P. Coste H. Bellevergue P. Grand-Perret T. Ajakane M. Baudet V. Boissin P. Boursier E. Loriolle F. Duhamel L. Charon D. Kirilovsky J. J. Biol. Chem. 1991; 266: 15771-15781Abstract Full Text PDF PubMed Google Scholar). Although all protein kinase C isoforms can be activated by phospholipids in various cell types, only protein kinases Cα and Cθ are rapidly translocated to the cell membrane of T lymphocytes following antigen-presenting cell recognition (70Szamel M. Appel A. Schwinzer R. Resch K. J. Immunol. 1998; 160: 2207-2214PubMed Google Scholar, 71Monks C.R.F. Kupfer H. Tamir I. Barlow A. Kupfer A. Nature. 1997; 385: 83-86Crossref PubMed Scopus (489) Google Scholar). Activation of protein kinase Cθ leads, in turn, to an increase in interleukin-2 receptor expression and activation of the MAPK c-Jun N-terminal kinase (70Szamel M. Appel A. Schwinzer R. Resch K. J. Immunol. 1998; 160: 2207-2214PubMed Google Scholar, 72Werlen G. Jacinto E. Xia Y. Karin M. EMBO J. 1998; 17: 3101-3111Crossref PubMed Scopus (252) Google Scholar). Because TCR ligation results in the membrane translocation of Cbl as well (45Hartley D. Corvera S. J. Biol. Chem. 1996; 271: 21939-21943Abstract Full Text Full Text PDF PubMed Scopus (49) Google Scholar), it is possible that protein kinase C binds to and directly phosphorylates Cbl (11Liu Y.-C. Altman A. Cell. Signaling. 1998; 10: 377-385Crossref PubMed Scopus (84) Google Scholar). Evidence that Cbl becomes serine-phosphorylated after PMA or TCR stimulation has been demonstrated by Liu et al. (37Liu Y.-C. Elly C. Yoshida H. Bonnefoy-Berard N. Altman A. J. Biol. Chem. 1996; 271: 14591-14595Abstract Full Text Full Text PDF PubMed Scopus (100) Google Scholar, 38Liu Y.-C. Liu Y. Elly C. Yoshida H. Lipkowitz S. Altman A. J. Biol. Chem. 1997; 272: 9979-9985Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). In these studies, TCR activation caused the serine phosphorylation of a serine-rich region of Cbl extending from amino acids 615 to 644 and enhanced the binding of Cbl to the 14-3-3 protein. However, it is also possible that protein kinase C acts indirectly, i.e. through an activation-dependent decrease in serine phosphatase or increase in tyrosine phosphatase activity. In this context, Cbl was found to be a substrate of the SH2 domain-containing phosphotyrosine phosphatase SHP-1 (73Uddin S. Gardziola C. Dangat A. Yi T. Platanias L.C. Biochem. Biophys. Res. Commun. 1996; 225: 833-838Crossref PubMed Scopus (30) Google Scholar). It will be important to determine whether the introduction of inactive forms of protein kinase C isozymes, particularly protein kinase Cθ, into T lymphocytes modulates Cbl tyrosine phosphorylation and blocks Cbl-CrkL dissociation.Reversible tyrosine phosphorylation is a critical mechanism for the regulation of signal transduction, cell growth, differentiation, and development. It is well established that protein kinase C-mediated serine/threonine phosphorylation of growth factor receptors causes an inhibition of receptor protein-tyrosine kinase activity (74Hunter T. Ling N. Cooper J.A. Nature. 1984; 311: 480-483Crossref PubMed Scopus (421) Google Scholar). In human 293 cells, the IRS-1 adaptor protein, which is extensively tyrosine-phosphorylated by the insulin receptor tyrosine kinase after insulin activation, also becomes serine-phosphorylated (75Sun A. Rothenberg P. Kahn C. Backer J. Araki E. Wilden P. Cahill D. Goldstein B. White M. Nature. 1991; 352: 73-76Crossref PubMed Scopus (1274) Google Scholar), which correlates with the decreased binding of IRS-1 to p85 (34De Fea K. Roth R.A. Biochemistry. 1997; 36: 181-189Crossref PubMed Scopus (222) Google Scholar). Activation of endogenous or transfected protein kinase C by PMA causes extensive serine phosphorylation of IRS-1, resulting in an inhibition of IRS-1 tyrosine phosphorylation by insulin (35De Fea K. Roth R.A. J. Biol. Chem. 1997; 272: 31400-31406Abstract Full Text Full Text PDF PubMed Scopus (266) Google Scholar) and the development of insulin resistance (76Hotamisligil G. Peraldi P. Budavari A. Ellis R. White M. Spiegelman B. Science. 1996; 271: 665-668Crossref PubMed Scopus (2177) Google Scholar). Similarly, it is well established that TCR ligation causes the tyrosine phosphorylation of phospholipase C-γ1, leading to activation of protein kinase C, which in turn phosphorylates phospholipase C-γ1 on serine residues and reverses tyrosine phosphorylation (77Park D.J. Min H.K. Rhee S.G J. Biol. Chem. 1992; 267: 1496-1501Abstract Full Text PDF PubMed Google Scholar). Also in T cells, PMA treatment reduces thein vitro and in vivo CD28 tyrosine phosphorylation from anti-CD28 antibody-stimulated cells (78Hutchcroft J.E. Tsai B. Bierer B.E. J. Biol. Chem. 1996; 271: 13362-13370Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar), resulting in interleukin-2 production. Thus, serine phosphorylation of several signaling proteins coincides with dephosphorylation of these proteins on tyrosine residues, an event that may provide a critical negative feedback signal for the inhibition of growth factor signaling. In a recent work by Finco et al. (79Finco T.S. Kadlecek T. Zhang W. Samelson L.E. Weiss A. Immunity. 1998; 9: 617-626Abstract Full Text Full Text PDF PubMed Scopus (439) Google Scholar), it has been show that the mutant Jurkat T cell line JCaM2 is deficient in pp36/LAT expression, resulting in defective TCR-mediated signal transduction. More important, these cells show an elevated tyrosine phosphorylation of Cbl and a significantly diminished phosphorylation of phospholipase C-γ1 and generation of inositol phosphates. It is conceivable that in the absence of LAT, phospholipase C-γ1-dependent activation of protein kinase C does not occur, mimicking the effect of protein kinase C inhibition by GF109203X on Cbl tyrosine phosphorylation. Further work will be required to test this hypothesis. T cell receptor (TCR) 1The abbreviations TCRT cell receptorPIphosphoinositideIRS-1insulin receptor substrate 1PMAphorbol 12-myristate 13-acetateMAPKmitogen-activated protein kinasePAGEpolyacrylamide gel electrophoresisMEKMAPK/extracellular receptor kinase kinase 1The abbreviations TCRT cell receptorPIphosphoinositideIRS-1insulin receptor substrate 1PMAphorbol 12-myristate 13-acetateMAPKmitogen-activated protein kinasePAGEpolyacrylamide gel electrophoresisMEKMAPK/extracellular receptor kinase kinaseligation by antigen-presenting cells or by antibodies to the CD3-TCR complex causes rapid increases in the activities of protein-tyrosine kinases and in the tyrosine phosphorylation of cellular substrates. The kinases involved belong to two families of nonreceptor protein-tyrosine kinases, the Src (Fyn and Lck) and Syk (Syk and ZAP-70) families (1Alberola-Ila J. Takaki S. Kerner J.D. Perlmutter R.M. Annu. Rev. Immunol. 1997; 15: 125-154Crossref PubMed Scopus (230) Google Scholar, 2Cantrell D.A. Annu. Rev. Immunol. 1996; 14: 259-274Crossref PubMed Scopus (592) Google Scholar, 3Wange R.L. Samelson L.E. Immunity. 1996; 5: 197-205Abstract Full Text Full Text PDF PubMed Scopus (460) Google Scholar). Activation of Lck and/or Fyn leads to the tyrosine phosphorylation of immunoreceptor tyrosine-based activation motifs present in the intracellular segments of the CD3 ε- and ζ-proteins (4Reth M. Nature. 1989; 338: 383-384Crossref PubMed Scopus (1154) Google Scholar, 5Samelson L.E. Klausner R.D. J. Biol. Chem. 1992; 267: 24913-24916Abstract Full Text PDF PubMed Google Scholar), followed by the recruitment, tyrosine phosphorylation, and activation of ZAP-70. This biochemical response couples the TCR to a diverse group of signal transduction molecules, including adaptor proteins, seri" @default.
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• W2079461939 date "1999-07-01" @default.
• W2079461939 modified "2023-10-01" @default.
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