Cbl-mediated Regulation of T Cell Receptor-induced AP1 Activation

Abstract

The functional role of Cbl in regulating T cell receptor (TCR)-mediated signal transduction pathways is unknown. This study uses Cbl overexpression in conjunction with a Ras-sensitive AP1 reporter construct to examine its role in regulating TCR-mediated activation of the Ras pathway. Cbl overexpression in Jurkat T cells inhibited AP1 activity after TCR ligation. However, AP1 induction by 4β-phorbol 12-myristate 13-acetate, which up-regulates Ras activity in a protein kinase C-dependent, TCR/tyrosine kinase-independent manner, was not affected by Cbl overexpression. Cbl overexpression also did not affect AP1 induction by an activated Ras protein or a membrane-bound form of the guanine nucleotide exchange factor Sos. In addition, activation of the mitogen-activated protein kinase Erk2 was decreased by Cbl overexpression. Therefore, Cbl regulates events that are required for full TCR-mediated Ras activation, and data are presented to support a model whereby Cbl regulates events required for Ras activation via its association with Grb2. The functional role of Cbl in regulating T cell receptor (TCR)-mediated signal transduction pathways is unknown. This study uses Cbl overexpression in conjunction with a Ras-sensitive AP1 reporter construct to examine its role in regulating TCR-mediated activation of the Ras pathway. Cbl overexpression in Jurkat T cells inhibited AP1 activity after TCR ligation. However, AP1 induction by 4β-phorbol 12-myristate 13-acetate, which up-regulates Ras activity in a protein kinase C-dependent, TCR/tyrosine kinase-independent manner, was not affected by Cbl overexpression. Cbl overexpression also did not affect AP1 induction by an activated Ras protein or a membrane-bound form of the guanine nucleotide exchange factor Sos. In addition, activation of the mitogen-activated protein kinase Erk2 was decreased by Cbl overexpression. Therefore, Cbl regulates events that are required for full TCR-mediated Ras activation, and data are presented to support a model whereby Cbl regulates events required for Ras activation via its association with Grb2. Perturbation of the T cell receptor (TCR) 1The abbreviations used are: TCR, T cell receptor; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; IL-2, interleukin-2; PMA, 4β-phorbol 12-myristate 13-acetate; HA, hemagglutinin; GST, glutathioneS-transferase; SEAP, secreted alkaline phosphatase. 1The abbreviations used are: TCR, T cell receptor; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; IL-2, interleukin-2; PMA, 4β-phorbol 12-myristate 13-acetate; HA, hemagglutinin; GST, glutathioneS-transferase; SEAP, secreted alkaline phosphatase. by antigen in the context of the appropriate major histocompatibility complex molecule initiates a cascade of events that involves the phosphorylation of proteins by tyrosine kinases (1Perlmutter R.M. Levin S.D. Appleby M.W. Anderson S.J. Alberola J. Annu. Rev. Immunol. 1993; 11: 451-499Crossref PubMed Scopus (190) Google Scholar). 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J. 1993; PubMed Scopus Google Scholar). the that on AP1 activation in T an the protein was with Jurkat of in of the protein but no on AP1 activation after with or not data that not affect AP1 In addition, these data that the of Cbl overexpression on AP1 activation the of This multiple including a for as by the of a protein a of this to with and J.A. Y. Langdon W.Y. Samelson L.E. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). T cell activation, is to the of the to the to with and Cbl and and in a to the of not and L. A. S. A. J. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Reedquist K.A. T. Soltoff S. Panchamoorthy G. Druker B. Cantley L. Shoelson S.E. Band H. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, H. D. Czech M.P. Mol. Cell. Biol. 1995; PubMed Scopus Google Scholar, M. R. J. T. D. Nature. 1993; PubMed Scopus Google Scholar). that Cbl regulate AP1 complex by Ras activation via the and to in a Jurkat cells with and for and with of the protein or a protein of the of Cbl by with an or Jurkat cells with and as for Jurkat cells with and for with an and by with an and with the the protein used for the used for and the used for Cbl to regulate the association of with to after activation, a of that with Sos. and L. A. S. A. J. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Reedquist K.A. T. Soltoff S. Panchamoorthy G. Druker B. Cantley L. Shoelson S.E. Band H. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. Y. Langdon W.Y. Samelson L.E. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google the of Cbl to with activation In T Cbl with the of as be by the of Cbl to with a protein of this Cbl with the of and not at all with the after activation the TCR and data not Activation of Jurkat cells with or for leads to a in the of Cbl with the protein and the protein The of Cbl is to of Cbl a or an to as by the of a protein of a of the of Cbl to of and activated Jurkat cells of Cbl was also observed Cbl was with by a that is a of T cell activation in Jurkat be with the of that associated with after activation The association of with after TCR engagement is with the data of S. Lee L. Ledbetter J.A. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google and U. Shoelson S.E. S.J. Mol. Cell. Biol. 1995; PubMed Google Scholar), found to for to data that Cbl and with an of and that Cbl regulate activation of the Ras in T by with for to the of Grb2. the of Cbl overexpression on Ras signaling T cell activation, the of activation of the Ras effector Erk2 was Erk2 is a mitogen-activated protein kinase that AP1 activation by the transcription factor which transcription H. Shaw Nature. PubMed Scopus Google Scholar, R. J. R. Cell. 1993; Full Text PDF PubMed Scopus Google Scholar). In T Ras is and for Erk2 activation M. S.J. Cantrell D. J. Exp. Med. 1993; PubMed Scopus Google Scholar). examine Erk2 activity in Jurkat cells with an Erk2 and or with as a The of activation of the Erk2 protein was by of the of in decreased activation in cells Cbl with cells of the was activated after In in which activation was by with an that the form of mitogen-activated protein cells Cbl a in the of with the not In to activation by was or in cells data that Cbl overexpression events required for Ras activation T cell The that the of the of Erk2 activation by Cbl overexpression was not as as that for AP1 activation and the two Cbl overexpression may Ras-sensitive pathways as the kinase that also to AP1 The that Cbl overexpression AP1 and Erk2 activation that Cbl regulates events that are critical for Ras signaling T cell activation and the of a role for Cbl in the of a signaling in T Cbl overexpression not affect AP1 activation by or constitutively activated Ras or that Cbl of data and the that Cbl with a of critical TCR-associated signaling as Lck, and L. A. S. A. J. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, D. S. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, T. Reedquist K.A. T. Soltoff S. Panchamoorthy G. Druker B. Cantley L. Shoelson S.E. Band H. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus Google Scholar, H. D. Czech M.P. Mol. Cell. Biol. 1995; PubMed Scopus Google M. D. R. A. J. Exp. Med. 1996; PubMed Scopus Google Scholar, Reedquist K.A. Miyake S. Langdon W.Y. Band H. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, J.A. Y. Langdon W.Y. Samelson L.E. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google that Cbl regulates activation The of multiple protein in with the association of Cbl with critical signaling and the of an enzymatic activity associated with as a In this Cbl may by an complex of effector and to TCR activation and signal transduction after receptor In such a complex in Cbl may also regulate the of as with this a is to that of the proteins in which form protein that activation of multiple effector M.C. Cell. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). of Cbl affect T cell activation by the of the activation an in the of Cbl may its to an of In addition, overexpression may Cbl to for the of to with of Cbl also with the of the the guanine nucleotide exchange factors and and L. A. S. A. J. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, S. G. Shoelson S.E. S.J. J. Immunol. 1996; Google Scholar, S. R. Mol. Cell. Biol. 1995; 16: Scopus Google Scholar, S. Lee S.J. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus (74) Google Scholar, A. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). and in Ras activation S. G. Shoelson S.E. S.J. J. Immunol. 1996; Google Scholar, L. A. S. A. J. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, S. Lee S.J. J. Biol. Chem. 1995; 270: Full Text Full Text PDF PubMed Scopus (74) Google Scholar, S. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). Therefore, Cbl may the association of these with proteins as of an exchange of Cbl for on that Cbl may by the association of with in T The responsible for the of Cbl after T cell is unknown, a of Cbl is Cbl is TCR a the early of Cbl phosphorylation that of the of Cbl is that Cbl phosphorylation a role in regulating its association with Grb2. However, the that Cbl after T cell activation, is at this in that factors in to tyrosine phosphorylation may to the of Cbl with J.A. Y. Langdon W.Y. Samelson L.E. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar). factors the of Cbl Y. Yeung Y.-G. Langdon W.Y. Stanley E.R. J. Biol. Chem. 1996; 271: 17-20Abstract Full Text Full Text PDF PubMed Scopus (135) Google Scholar), phosphorylation of and/or by the association of Cbl with The of and Samelson Y. Samelson L. Science. PubMed Scopus Google Scholar), which that Cbl overexpression in cells has a on Syk phosphorylation and to the that Cbl may be to the activity of the kinases with which Although Cbl to with Syk to regulate its to be this is to Cbl the activity of Syk or is by a of Syk by Cbl overexpression. Cbl has the to with ZAP-70 and phospholipase be important to Cbl regulates the of the kinases with which and Cbl regulates the activation of these as (15Donovan J.A. Wange R.L. Langdon W.Y. Samelson L.E. J. Biol. Chem. 1994; 269: 22921-22924Abstract Full Text PDF PubMed Google Scholar, M. D. R. A. J. Exp. Med. 1996; PubMed Scopus Google Scholar, Reedquist K.A. Miyake S. Langdon W.Y. Band H. J. Biol. Chem. 1996; 271: Full Text Full Text PDF PubMed Scopus Google Scholar, A. J. Biol. Chem. 1994; 269: Full Text PDF PubMed Google Scholar). data are with and the by C. Langdon W.Y. Altman A. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar), which that of the Cbl protein in Jurkat cells activity to a in Jurkat cells and in cells with The of to this was to be inhibited by a form of The of the protein by the as as activation of AP1 the Ras signaling pathway. Therefore, these that of leads to AP1 activation, which with activity to of an to of an reporter found that of the the activity of the reporter used in in and Jurkat L. and in the or the reporter protein by the two AP1 reporter used in these for the observed two in the of to AP1 The by which Ras activation is unknown, the that is constitutively that may as a constitutively form of with its not of Cbl overexpression on This is with that Cbl regulates activation to the TCR and has no on the of downstream such as protein kinase C or by or The that Cbl overexpression leads to a of TCR-mediated signaling events is also with of the of Cbl overexpression on receptor signaling H. Sasaki K. Miyagawa K. H. Mitani K. Yazaki Y. Hirai H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Langdon W.Y. 1995; 11: Google Scholar). that overexpression of Cbl in leads to a in phosphorylation and in the of that associated with the after The study by Ueno H. Sasaki K. Miyagawa K. H. Mitani K. Yazaki Y. Hirai H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google also that Cbl regulate activation of the signaling pathway. However, study H. Sasaki K. Miyagawa K. H. Mitani K. Yazaki Y. Hirai H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, Langdon W.Y. 1995; 11: Google was to on activation of the Ras pathway. This with results is by the that the role of Cbl in signaling pathways may be cell and the of Cbl and in cell or not Cbl with for to Grb2. This may be the in and Langdon Langdon W.Y. 1995; 11: Google found a association of Cbl with in This that Cbl has a of association with in with T cells because of its to that of or because of a that regulates the of Cbl to to in Ueno H. Sasaki K. Miyagawa K. H. Mitani K. Yazaki Y. Hirai H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google also that activation of the Ras may by an kinase-independent because the kinase activity of the receptor for that of the H. Sasaki K. Miyagawa K. H. Mitani K. Yazaki Y. Hirai H. J. Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar). Ras activation via the receptor is affected by Cbl overexpression to be Although a of data that Cbl as a complex molecule in all cell types, is known the of Cbl in hematopoietic In addition, data that the signaling pathways Cbl regulates are cell and that its of is on the of of effector in cell the of Cbl in T cells to a to the TCR and of form a for of the of Cbl in activation in the hematopoietic cell for the and for Langdon for the for the protein for protein for the and for the Jurkat T cell and Samelson for of the