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

G. A. Evans, M. A. Goldsmith, J. A. Johnston, W. Xu, S. R. Weiler, R. Erwin, O. M. Z. Howard, R. T. Abraham, J. O. John, W. C. Greene, W. L. Farrar
1995 Journal of Biological Chemistry  
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 ␤ (IL-2R␤) chain is the critical receptor component required to mediate this effect. The use of IL-2R␤ chain deletion mutants transfected into a Ba/F3 murine cell model describes a requirement for the IL-2R␤ "acid-rich" domain between amino acids 315 and 384 for Shc tyrosine phosphorylation and receptor
more » ... eceptor association. COS cell co-transfection studies of IL-2R␤ 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 acidrich domain of the IL-2R␤ 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␤ 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␤ 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.
doi:10.1074/jbc.270.48.28858 pmid:7829527 fatcat:dhov6mx6frgdpg5xjsf3ld3bgu