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https://hdl.handle.net/2440/9561
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Type: | Journal article |
Title: | The role of disulfide-linked dimerization in interleukin-3 receptor signaling and biological activity |
Author: | Le, F. Stomski, F. Woodcock, J. Lopez, A. Gonda, T. |
Citation: | Journal of Biological Chemistry, 2000; 275(7):5124-5130 |
Publisher: | Amer Soc Biochemistry Molecular Biology Inc |
Issue Date: | 2000 |
ISSN: | 0021-9258 1083-351X |
Statement of Responsibility: | Fei Le, Frank Stomski, Joanna M. Woodcock, Angel F. Lopez and Thomas J. Gonda |
Abstract: | Cysteine residues 86 and 91 of the beta subunit of the human interleukin (hIL)-3 receptor (hbetac) participate in disulfide-linked receptor subunit heterodimerization. This linkage is essential for receptor tyrosine phosphorylation, since the Cys-86 --> Ala (Mc4) and Cys-91 --> Ala (Mc5) mutations abolished both events. Here, we used these mutants to examine whether disulfide-linked receptor dimerization affects the biological and biochemical activities of the IL-3 receptor. Murine T cells expressing hIL-3Ralpha and Mc4 or Mc5 did not proliferate in hIL-3, whereas cells expressing wild-type hbetac exhibited rapid proliferation. However, a small subpopulation of cells expressing each mutant could be selected for growth in IL-3, and these proliferated similarly to cells expressing wild-type hbetac, despite failing to undergo IL-3-stimulated hbetac tyrosine phosphorylation. The Mc4 and Mc5 mutations substantially reduced, but did not abrogate, IL-3-mediated anti-apoptotic activity in the unselected populations. Moreover, the mutations abolished IL-3-induced JAK2, STAT, and AKT activation in the unselected cells, whereas activation of these molecules in IL-3-selected cells was normal. In contrast, Mc4 and Mc5 showed a limited effect on activation of Erk1 and -2 in unselected cells. These data suggest that whereas disulfide-mediated cross-linking and hbetac tyrosine phosphorylation are normally important for receptor activation, alternative mechanisms can bypass these requirements. |
Keywords: | Cell Line Animals Humans Mice Disulfides Cysteine Receptors, Interleukin-3 Proto-Oncogene Proteins Transcription Factors Signal Transduction MAP Kinase Signaling System Mutagenesis Dimerization Proto-Oncogene Proteins c-akt Protein-Tyrosine Kinases Janus Kinase 2 Protein Serine-Threonine Kinases |
DOI: | 10.1074/jbc.275.7.5124 |
Published version: | http://dx.doi.org/10.1074/jbc.275.7.5124 |
Appears in Collections: | Aurora harvest Medicine publications |
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