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Molecular and Cellular Biology, March 2003, p. 2017-2028, Vol. 23, No. 6
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.6.2017-2028.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Phosphorylation-Dependent Regulation of T-Cell Activation by PAG/Cbp, a Lipid Raft-Associated Transmembrane Adaptor

Dominique Davidson,1 Marcin Bakinowski,1 Matthew L. Thomas,2,{dagger} Vaclav Horejsi,3 and André Veillette1,4,5,6,7*

Laboratory of Molecular Oncology, IRCM,1 Department of Medicine, University of Montréal,4 Departments of Biochemistry,5 Microbiology and Immunology,6 Medicine, McGill University, Montréal, Québec, Canada,7 Howard Hughes Medical Institute, Department of Pathology, Washington University School of Medicine, St. Louis, Missouri,2 Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague, Czech Republic3

Received 30 October 2002/ Returned for modification 16 December 2002/ Accepted 24 December 2002

PAG/Cbp (hereafter named PAG) is a transmembrane adaptor molecule found in lipid rafts. In resting human T cells, PAG is tyrosine phosphorylated and associated with Csk, an inhibitor of Src-related protein tyrosine kinases. These modifications are rapidly lost in response to T-cell receptor (TCR) stimulation. Overexpression of PAG was reported to inhibit TCR-mediated responses in Jurkat T cells. Herein, we have examined the physiological relevance and the mechanism of PAG-mediated inhibition in T cells. Our studies showed that PAG tyrosine phosphorylation and association with Csk are suppressed in response to activation of normal mouse T cells. By expressing wild-type and phosphorylation-defective (dominant-negative) PAG polypeptides in these cells, we found that the inhibitory effect of PAG is dependent on its capacity to be tyrosine phosphorylated and to associate with Csk. PAG-mediated inhibition was accompanied by a repression of proximal TCR signaling and was rescued by expression of a constitutively activated Src-related kinase, implying that it is due to an inactivation of Src kinases by PAG-associated Csk. We also attempted to identify the protein tyrosine phosphatases (PTPs) responsible for dephosphorylating PAG in T cells. Through cell fractionation studies and analyses of genetically modified mice, we established that PTPs such as PEP and SHP-1 are unlikely to be involved in the dephosphorylation of PAG in T cells. However, the transmembrane PTP CD45 seems to play an important role in this process. Taken together, these data provide firm evidence that PAG is a bona fide negative regulator of T-cell activation as a result of its capacity to recruit Csk. They also suggest that the inhibitory function of PAG in T cells is suppressed by CD45. Lastly, they support the idea that dephosphorylation of proteins on tyrosine residues is critical for the initiation of T-cell activation.

* Corresponding author. Mailing address: Laboratory of Molecular Oncology, IRCM, 110 Pine Ave. West, Montréal, Québec, Canada H2W 1R7. Phone: (514) 987-5561. Fax: (514) 987-5562. E-mail: veillea{at}ircm.qc.ca.

{dagger} Deceased.

Molecular and Cellular Biology, March 2003, p. 2017-2028, Vol. 23, No. 6
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.6.2017-2028.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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