Activation of JAK3, but not JAK1, is critical for IL-2-induced proliferation and STAT5 recruitment by a COOH-terminal region of the IL-2 receptor β-chain

A number of cytokines and growth factors use the JAK-STAT pathway to signal from the cell membrane to the nucleus. While homodimerizing cytokine receptors may transmit signal via a single form of JAK (i.e. growth hormone receptors), several multicomponent cytokine receptors have been shown to requir...

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Bibliographic Details
Published in:Cytokine (Philadelphia, Pa.) Pa.), 1995-10, Vol.7 (7), p.689-700
Main Authors: Kirken, Robert A., Rui, Hallgeir, Malabarba, Grazia M., Howard, Zack O.M., Kawamura, Masura, O 'Shea, John J., Farrar, William L.
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Catalysis
Cell Line
Enzyme Activation
Evaluation Studies as Topic
Humans
IL-2 receptor
JAK1
JAK3
Janus Kinase 1
Janus Kinase 3
Lymphocyte Activation - physiology
Mice
Mitogens - physiology
Molecular Sequence Data
Phosphorylation
Protein-Tyrosine Kinases - metabolism
Receptors, Interleukin-2 - metabolism
Signal Transduction - physiology
STAT5
T-Lymphocytes - metabolism
Transcription Factors - biosynthesis
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Summary:A number of cytokines and growth factors use the JAK-STAT pathway to signal from the cell membrane to the nucleus. While homodimerizing cytokine receptors may transmit signal via a single form of JAK (i.e. growth hormone receptors), several multicomponent cytokine receptors have been shown to require simultaneous activation of pairs of different JAK kinases (i.e. interferon receptors). Recent evidence for a preferential coupling of JAK3 to interleukin-2 receptor- γ (IL-2R γ) and JAK1 to IL-2R β supports the concept of heterotransactivation of JAK1 and JAK3 caused by IL-2-induced heterodimerization of their receptor partners. The present study verified the ability of IL-2 to cause tyrosine phosphorylation and activation of JAK1 and JAK3, but demonstrated that IL-2 stimulated JAK3 to a significantly larger extent than JAK1 in human T Iymphocytes and the YT cell line. This conclusion was based upon several independent criteria, including more vigorous tyrosine phosphorylation of JAK3, more marked enzymatic activation of JAK3 as well as higher abundance of JAK3 in activated IL-2 receptor complexes. Furthermore, when human IL-2R β was stably expressed in murine BA/F3 cells, robust IL-2-induced proliferation and JAK3 activation occurred without detectable involvement of either JAK1, JAK2 or TYK2. We therefore propose that IL-2 receptor signal transduction does not depend on equimolar heterodimerization of JAK1 and JAK3 following IL-2-induced heterodimerization of IL-2R β and IL-2R γ. Nonetheless, a membrane-proximal region of human IL-2R β (Asn 240-Leu 335) was critical for JAK3 activation, and the amount of JAK3 present in activated IL-2 receptor complexes increased with time, suggesting that stabilization of JAK3 binding to the receptor complex relies on both IL-2R β and IL-2R γ. Moreover, STAT5 was found to be the predominant STAT transcription factor used by IL-2 in human T cells, and specifically required a COOH-terminal region of IL-2R β (Ser 386-Val 525), while STAT5 recruitment was not correlated to activation of IL-2R γ or JAK3.
ISSN:1043-4666
1096-0023
DOI:10.1006/cyto.1995.0081