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Analysis of interleukin-2-dependent signal transduction through the Shc/Grb2 adapter pathway. Interleukin-2-dependent mitogenesis does not require Shc phosphorylation or receptor association.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 1995 Dec 01; Vol. 270 (48), pp. 28858-63. - Publication Year :
- 1995
-
Abstract
- The interleukin (IL)-2 receptor system has previously been shown to signal through the association and tyrosine phosphorylation of Shc. This study demonstrates that the IL-2 receptor beta (IL-2R beta) chain is the critical receptor component required to mediate this effect. The use of IL-2R beta chain deletion mutants transfected into a Ba/F3 murine cell model describes a requirement for the IL-2R beta "acid-rich" domain between amino acids 315 and 384 for Shc tyrosine phosphorylation and receptor association. COS cell co-transfection studies of IL-2R beta chain constructs containing point mutations of tyrosine to phenylalanine along with the tyrosine kinase Jak-1 and a hemagglutinin-tagged Shc revealed that the motif surrounding phosphorylated tyrosine 338 within the acid-rich domain of the IL-2R beta is a binding site for Shc. Deletion of this domain has previously been shown to abrogate the ability of IL-2 to activate Ras but does not affect IL-2-dependent mitogenesis in the presence of serum. Proliferation assays of Ba/F3 cells containing IL-2R beta chain deletion mutants in serum-free medium with or without insulin shows that deletion of the acid-rich domain does not affect IL-2-driven mitogenesis regardless of the culture conditions. This study thus defines the critical domain within the IL-2R beta chain required to mediate Shc binding and Shc tyrosine phosphorylation and further shows that Shc binding and phosphorylation are not required for IL-2-dependent mitogenesis. Neither serum nor insulin is required to supplement the loss of induction of the Shc adapter or Ras pathways, which therefore suggests a novel mechanism for mitogenic signal transduction mediated by this hematopoietin receptor.
- Subjects :
- Amino Acid Sequence
Animals
Binding Sites
Cell Line
Cells, Cultured
GRB2 Adaptor Protein
Humans
Mice
Molecular Sequence Data
Phosphorylation
Protein Binding
Shc Signaling Adaptor Proteins
Src Homology 2 Domain-Containing, Transforming Protein 1
Tyrosine metabolism
Adaptor Proteins, Signal Transducing
Adaptor Proteins, Vesicular Transport
Interleukin-2 metabolism
Mitosis
Proteins metabolism
Receptors, Interleukin-2 metabolism
Signal Transduction
Subjects
Details
- Language :
- English
- ISSN :
- 0021-9258
- Volume :
- 270
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 7499411
- Full Text :
- https://doi.org/10.1074/jbc.270.48.28858