GROWTH SIGNAL-TRANSDUCTION BY THE HUMAN INTERLEUKIN-2 RECEPTOR REQUIRES CYTOPLASMIC TYROSINES OF THE BETA-CHAIN AND NONTYROSINE RESIDUES OFTHE GAMMA(C) CHAIN
Ma. Goldsmith et al., GROWTH SIGNAL-TRANSDUCTION BY THE HUMAN INTERLEUKIN-2 RECEPTOR REQUIRES CYTOPLASMIC TYROSINES OF THE BETA-CHAIN AND NONTYROSINE RESIDUES OFTHE GAMMA(C) CHAIN, The Journal of biological chemistry, 270(37), 1995, pp. 21729-21737
To evaluate the possible role for receptor-based tyrosine phosphorylat
ion in growth signaling induced by interleukin-2 (IL-2), a series of s
ubstitution tyrosine mutants of the IL-2 receptor beta and gamma(c) ch
ains was prepared and analyzed. Concurrent mutation of all six of the
cytoplasmic tyrosines present in the beta chain markedly inhibited IL-
2-induced growth signaling in both pro-B and T cell lines. Growth sign
aling in a pro-B cell line was substantially reconstituted when either
of the two distal tyrosines (Tyr-392, Tyr-510) was selectively restor
ed in the tyrosine-negative beta mutant, whereas reconstitution of the
proximal tyrosines (Tyr-338, Tyr-355, Tyr-358, Tyr-361) did not resto
re this signaling function. Furthermore, at least one of the two cytop
lasmic tyrosines that is required for beta 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 o
f the beta chain likewise were important for growth signaling in T cel
ls. In contrast, although the gamma(c) subunit is a target for tyrosin
e phosphorylation in vivo, concurrent substitution of all four cytopla
smic 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 gamma(c) abrogated rec
eptor function. Therefore, tyrosine residues of beta but not of gamma(
c) appear to play a pivotal role in regulating growth signal transduct
ion through the IL-2 receptor, either by influencing cytoplasmic domai
n folding or by serving as sites for phosphorylation and subsequent as
sociation with signaling intermediates. These findings thus highlight
a fundamental difference in the structural requirements for IL-2R beta
and gamma(c) in receptor-mediated signal transduction.