Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the β chain and non-tyrosine residues of the γ(c) chain

M. A. Goldsmith, S. Y. Lai, W. Xu, M. C. Amaral, E. S. Kuczek, L. J. Parent, Gordon Mills, K. L. Tarr, G. D. Longmore, W. C. Greene

Research output: Contribution to journalArticle

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Abstract

To evaluate the possible role for receptor-based tyrosine phosphorylation in growth signaling induced by interleukin-2 (IL-2), a series of substitution tyrosine mutants of the IL-2 receptor β and γ(c) chains was prepared and analyzed. Concurrent mutation of all six of the cytoplasmic tyrosines present in the β chain markedly inhibited IL-2-induced growth signaling in both pro- B and T cell lines. Growth signaling in a pro-B cell line was substantially reconstituted when either of the two distal tyrosines (Tyr-392, Tyr-510) was selectively restored in the tyrosine-negative β mutant, whereas reconstitution of the proximal tyrosines (Tyr-338, Tyr-355, Tyr-358, Tyr- 361) did not restore this signaling function. Furthermore, at least one of the two cytoplasmic tyrosines that is required for β chain function was found to serve as a phosphate acceptor site upon induction with IL-2. Studies employing a chimeric receptor system revealed that tyrosine residues of the β chain likewise were important for growth signaling in T cells. In contrast, although the γ(c) subunit is a target for tyrosine phosphorylation in vivo, concurrent substitution of all four cytoplasmic tyrosines of this chain produced no significant effect on growth signaling by chimeric IL-2 receptors. However, deletion of either the Box 1, Box 2, or intervening (V- Box) regions of γ(c) abrogated receptor function. Therefore, tyrosine residues of β but not of γ(c) appear to play a pivotal role in regulating growth signal transduction through the IL-2 receptor, either by influencing cytoplasmic domain folding or by serving as sites for phosphorylation and subsequent association with signaling intermediates. These findings thus highlight a fundamental difference in the structural requirements for IL- 2Rβ and γ(c) in receptor-mediated signal transduction.

Original languageEnglish (US)
Pages (from-to)21729-21737
Number of pages9
JournalJournal of Biological Chemistry
Volume270
Issue number37
DOIs
StatePublished - Jan 1 1995
Externally publishedYes

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Signal transduction
Interleukin-2 Receptors
Tyrosine
Signal Transduction
Growth
Phosphorylation
Interleukin-2
B-Lymphoid Precursor Cells
T-cells
Substitution reactions
T-Lymphocytes
Cell Line
Phosphates
Cells
Association reactions

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the β chain and non-tyrosine residues of the γ(c) chain. / Goldsmith, M. A.; Lai, S. Y.; Xu, W.; Amaral, M. C.; Kuczek, E. S.; Parent, L. J.; Mills, Gordon; Tarr, K. L.; Longmore, G. D.; Greene, W. C.

In: Journal of Biological Chemistry, Vol. 270, No. 37, 01.01.1995, p. 21729-21737.

Research output: Contribution to journalArticle

Goldsmith, M. A. ; Lai, S. Y. ; Xu, W. ; Amaral, M. C. ; Kuczek, E. S. ; Parent, L. J. ; Mills, Gordon ; Tarr, K. L. ; Longmore, G. D. ; Greene, W. C. / Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the β chain and non-tyrosine residues of the γ(c) chain. In: Journal of Biological Chemistry. 1995 ; Vol. 270, No. 37. pp. 21729-21737.
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abstract = "To evaluate the possible role for receptor-based tyrosine phosphorylation in growth signaling induced by interleukin-2 (IL-2), a series of substitution tyrosine mutants of the IL-2 receptor β and γ(c) chains was prepared and analyzed. Concurrent mutation of all six of the cytoplasmic tyrosines present in the β chain markedly inhibited IL-2-induced growth signaling in both pro- B and T cell lines. Growth signaling in a pro-B cell line was substantially reconstituted when either of the two distal tyrosines (Tyr-392, Tyr-510) was selectively restored in the tyrosine-negative β mutant, whereas reconstitution of the proximal tyrosines (Tyr-338, Tyr-355, Tyr-358, Tyr- 361) did not restore this signaling function. Furthermore, at least one of the two cytoplasmic tyrosines that is required for β chain function was found to serve as a phosphate acceptor site upon induction with IL-2. Studies employing a chimeric receptor system revealed that tyrosine residues of the β chain likewise were important for growth signaling in T cells. In contrast, although the γ(c) subunit is a target for tyrosine phosphorylation in vivo, concurrent substitution of all four cytoplasmic tyrosines of this chain produced no significant effect on growth signaling by chimeric IL-2 receptors. However, deletion of either the Box 1, Box 2, or intervening (V- Box) regions of γ(c) abrogated receptor function. Therefore, tyrosine residues of β but not of γ(c) appear to play a pivotal role in regulating growth signal transduction through the IL-2 receptor, either by influencing cytoplasmic domain folding or by serving as sites for phosphorylation and subsequent association with signaling intermediates. These findings thus highlight a fundamental difference in the structural requirements for IL- 2Rβ and γ(c) in receptor-mediated signal transduction.",
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T1 - Growth signal transduction by the human interleukin-2 receptor requires cytoplasmic tyrosines of the β chain and non-tyrosine residues of the γ(c) chain

AU - Goldsmith, M. A.

AU - Lai, S. Y.

AU - Xu, W.

AU - Amaral, M. C.

AU - Kuczek, E. S.

AU - Parent, L. J.

AU - Mills, Gordon

AU - Tarr, K. L.

AU - Longmore, G. D.

AU - Greene, W. C.

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N2 - To evaluate the possible role for receptor-based tyrosine phosphorylation in growth signaling induced by interleukin-2 (IL-2), a series of substitution tyrosine mutants of the IL-2 receptor β and γ(c) chains was prepared and analyzed. Concurrent mutation of all six of the cytoplasmic tyrosines present in the β chain markedly inhibited IL-2-induced growth signaling in both pro- B and T cell lines. Growth signaling in a pro-B cell line was substantially reconstituted when either of the two distal tyrosines (Tyr-392, Tyr-510) was selectively restored in the tyrosine-negative β mutant, whereas reconstitution of the proximal tyrosines (Tyr-338, Tyr-355, Tyr-358, Tyr- 361) did not restore this signaling function. Furthermore, at least one of the two cytoplasmic tyrosines that is required for β chain function was found to serve as a phosphate acceptor site upon induction with IL-2. Studies employing a chimeric receptor system revealed that tyrosine residues of the β chain likewise were important for growth signaling in T cells. In contrast, although the γ(c) subunit is a target for tyrosine phosphorylation in vivo, concurrent substitution of all four cytoplasmic tyrosines of this chain produced no significant effect on growth signaling by chimeric IL-2 receptors. However, deletion of either the Box 1, Box 2, or intervening (V- Box) regions of γ(c) abrogated receptor function. Therefore, tyrosine residues of β but not of γ(c) appear to play a pivotal role in regulating growth signal transduction through the IL-2 receptor, either by influencing cytoplasmic domain folding or by serving as sites for phosphorylation and subsequent association with signaling intermediates. These findings thus highlight a fundamental difference in the structural requirements for IL- 2Rβ and γ(c) in receptor-mediated signal transduction.

AB - To evaluate the possible role for receptor-based tyrosine phosphorylation in growth signaling induced by interleukin-2 (IL-2), a series of substitution tyrosine mutants of the IL-2 receptor β and γ(c) chains was prepared and analyzed. Concurrent mutation of all six of the cytoplasmic tyrosines present in the β chain markedly inhibited IL-2-induced growth signaling in both pro- B and T cell lines. Growth signaling in a pro-B cell line was substantially reconstituted when either of the two distal tyrosines (Tyr-392, Tyr-510) was selectively restored in the tyrosine-negative β mutant, whereas reconstitution of the proximal tyrosines (Tyr-338, Tyr-355, Tyr-358, Tyr- 361) did not restore this signaling function. Furthermore, at least one of the two cytoplasmic tyrosines that is required for β chain function was found to serve as a phosphate acceptor site upon induction with IL-2. Studies employing a chimeric receptor system revealed that tyrosine residues of the β chain likewise were important for growth signaling in T cells. In contrast, although the γ(c) subunit is a target for tyrosine phosphorylation in vivo, concurrent substitution of all four cytoplasmic tyrosines of this chain produced no significant effect on growth signaling by chimeric IL-2 receptors. However, deletion of either the Box 1, Box 2, or intervening (V- Box) regions of γ(c) abrogated receptor function. Therefore, tyrosine residues of β but not of γ(c) appear to play a pivotal role in regulating growth signal transduction through the IL-2 receptor, either by influencing cytoplasmic domain folding or by serving as sites for phosphorylation and subsequent association with signaling intermediates. These findings thus highlight a fundamental difference in the structural requirements for IL- 2Rβ and γ(c) in receptor-mediated signal transduction.

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