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Molecular and Cellular Biology, June 2000, p. 4371-4380, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Hierarchy of Protein Tyrosine Kinases in Interleukin-2 (IL-2) Signaling: Activation of Syk Depends on Jak3; However, Neither Syk nor Lck Is Required for IL-2-Mediated STAT Activation

Yong-Jie Zhou,1,* Kelly S. Magnuson,2 Tammy P. Cheng,3 Massimo Gadina,1 David M. Frucht,1 Jerome Galon,1 Fabio Candotti,4 Robert L. Geahlen,5 Paul S. Changelian,2 and John J. O'Shea1

Lymphocyte Cell Biology Section, Arthritis and Rheumatism Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases,1 Howard Hughes Medical Institute-National Institutes of Health Research Scholars Program,3 and Clinical Gene Therapy Branch, National Human Genome Research Institute,4 National Institutes of Health, Bethesda, Maryland 20892; Department of Immunology, Pfizer Central Research, Groton, Connecticut 063402; and Department of Medicinal Chemistry and Molecular Pharmacology, Purdue University, West Lafayette, Indiana 479075

Received 4 February 2000/Accepted 15 March 2000

Interleukin-2 (IL-2) activates several different families of tyrosine kinases, but precisely how these kinases interact is not completely understood. We therefore investigated the functional relationships among Jak3, Lck, and Syk in IL-2 signaling. We first observed that in the absence of Jak3, both Lck and Syk had the capacity to phosphorylate Stat3 and Stat5a. However, neither supported IL-2-induced STAT activation, nor did dominant negative alleles of these kinases inhibit. Moreover, pharmacological abrogation of Lck activity did not inhibit IL-2-mediated phosphorylation of Jak3 and Stat5a. Importantly, ligand-dependent Syk activation was dependent on the presence of catalytically active Jak3, whereas Lck activation was not. Interestingly, Syk functioned as a direct substrate of Jak1 but not Jak3. Additionally, Jak3 phosphorylated Jak1, whereas the reverse was not the case. Taken together, our data support a model in which Lck functions in parallel with Jak3, while Syk functions as a downstream element of Jaks in IL-2 signaling. Jak3 may regulate Syk catalytic activity indirectly via Jak1. However, IL-2-mediated Jak3/Stat activation is not dependent on Lck or Syk. While the essential roles of Jak1 and Jak3 in signaling by gamma c-utilizing cytokines are clear, it will be important to dissect the exact contributions of Lck and Syk in mediating the effects of IL-2 and related cytokines.

* Corresponding author. Mailing address: ARB/NIAMS/NIH, 10/9N228, 10 Center Dr., MSC 1820, Bethesda, MD 20892-1820. Phone: (301) 496-2541. Fax: (301) 402-0012. E-mail: zhouy{at}exchange.nih.gov.

Molecular and Cellular Biology, June 2000, p. 4371-4380, Vol. 20, No. 12
0270-7306/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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