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Molecular and Cellular Biology, November 2003, p. 7667-7677, Vol. 23, No. 21
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.21.7667-7677.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Critical Role of Ser-520 Phosphorylation for Membrane Recruitment and Activation of the ZAP-70 Tyrosine Kinase in T Cells

Yaoming Yang,1 Patricia Villain,1 Tomas Mustelin,2 and Clément Couture1,3,4*

Program of Signal Transduction, Burnham Institute, La Jolla, California,2 Molecular Oncology Group, Lady Davis Institute for Medical Research,1 Departments of Medicine, Microbiology and Immunology, McGill University,3 Division of Hematology-Oncology, Sir Mortimer B. Davis Jewish General Hospital, Montreal, Canada4

Received 28 April 2003/ Returned for modification 13 June 2003/ Accepted 22 July 2003

Regulation of protein tyrosine kinases (PTKs) by tyrosine phosphorylation is well recognized; in fact, nearly all PTKs require phosphorylation of tyrosine residues in their "activation loop" for catalytic activity. In contrast, the phosphorylation of PTKs on serine and threonine residues has not been studied nearly as much. We report that the ZAP-70 PTK contains predominately phosphoserine in normal T lymphocytes as well as in Jurkat T leukemia cells. We have identified one site of phosphorylation as Ser-520 and find this site to be important for the recruitment and activation of ZAP-70 in T cells. Mutant ZAP-70-S520A had reduced ability to autophosphorylate and to mediate antigen receptor-induced interleukin 2 gene activation and was not enriched at the plasma membrane. These defects were rescued by addition of a myristylation signal to the N terminus of ZAP-70-S520A to force its plasma membrane and lipid raft localization. We conclude that phosphorylation of ZAP-70 at Ser-520 plays an important role in the correct localization of ZAP-70 and in priming ZAP-70 for its acute recruitment and activation upon antigen receptor ligation.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, 3755 Côte Ste-Catherine Rd., Montréal, QC, Canada H3T 1E2. Phone: (514) 340-8260. Fax: (514) 340-7573. E-mail: ccouture{at}ldi.jgh.mcgill.ca.

Molecular and Cellular Biology, November 2003, p. 7667-7677, Vol. 23, No. 21
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.21.7667-7677.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.





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