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

J Biol Chem. 1995 Dec 1;270(48):28858-63. doi: 10.1074/jbc.270.48.28858.


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.

MeSH terms

  • Adaptor Proteins, Signal Transducing*
  • Adaptor Proteins, Vesicular Transport*
  • Amino Acid Sequence
  • Animals
  • Binding Sites
  • Cell Line
  • Cells, Cultured
  • GRB2 Adaptor Protein
  • Humans
  • Interleukin-2 / metabolism*
  • Mice
  • Mitosis*
  • Molecular Sequence Data
  • Phosphorylation
  • Protein Binding
  • Proteins / metabolism*
  • Receptors, Interleukin-2 / metabolism*
  • Shc Signaling Adaptor Proteins
  • Signal Transduction*
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Tyrosine / metabolism


  • Adaptor Proteins, Signal Transducing
  • Adaptor Proteins, Vesicular Transport
  • GRB2 Adaptor Protein
  • GRB2 protein, human
  • Grb2 protein, mouse
  • Interleukin-2
  • Proteins
  • Receptors, Interleukin-2
  • SHC1 protein, human
  • Shc Signaling Adaptor Proteins
  • Shc1 protein, mouse
  • Src Homology 2 Domain-Containing, Transforming Protein 1
  • Tyrosine