Interleukin-7 induces the association of phosphatidylinositol 3-kinase with the alpha chain of the interleukin-7 receptor

Eur J Immunol. 1994 Sep;24(9):2168-74. doi: 10.1002/eji.1830240935.


The recently characterized receptor for interleukin (IL)-7 (IL-7R) includes a unique alpha chain as well as a common gamma chain shared with the receptors for IL-2 and IL-4. Engagement of the IL-7R activates the intracellular enzyme phosphatidylinositol (PtdIns) 3-kinase but the mechanism of PtdIns 3-kinase activation and the molecular basis of its interaction with IL-7R are not known. Here we show that IL-7 causes the 85-kDa regulatory subunit of PtdIns 3-kinase (p85), and PtdIns 3-kinase activity, to associate with the IL-7R. This interaction can be ascribed to ligand-induced phosphorylation of a single Tyr residue in the receptor's unique alpha chain. Herbimycin A, a specific protein tyrosine kinase inhibitor, suppresses not only tyrosine phosphorylation of the IL-7R but also its association with p85. A phosphopeptide corresponding to the sequence surrounding Tyr449 in the cytoplasmic tail of the IL-7R alpha chain, but not its non-phosphorylated analogue or phosphopeptides coincident with the sequences surrounding other alpha chain Tyr residues, efficiently competes out p85 binding. Replacement of Tyr449 with Phe results in a loss of p85 binding. Finally, soluble forms of the src homology 2 domains of p85, which bind directly to phosphotyrosyl peptides, specifically inhibit the association of p85 with the IL-7R. Thus, PtdIns 3-kinase recruitment occurs through a single, phosphotyrosine dependent recognition motif surrounding Tyr449 in the IL-7R alpha chain. This motif corresponds to a canonical sequence for p85 binding, Tyr(P)-X-X-Met. Since the closely related IL-2R and IL-4R also activate PtdIns 3-kinase but are devoid of such canonical motifs, our results suggest that the mechanism by which IL-7R recruits and activates PtdIns 3-kinase differs fundamentally from that used by the other receptors. PtdIns 3-kinase may, therefore, play a unique and important role in the biological response to IL-7.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Enzyme Activation / immunology
  • Glutathione Transferase
  • Humans
  • Immunoblotting
  • Interleukin-7 / physiology*
  • Molecular Sequence Data
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Phosphotyrosine
  • Precipitin Tests
  • Protein Binding / immunology
  • Receptors, Interleukin / chemistry
  • Receptors, Interleukin / metabolism*
  • Receptors, Interleukin-7
  • Recombinant Fusion Proteins
  • Tyrosine / analogs & derivatives
  • Tyrosine / metabolism


  • Interleukin-7
  • Receptors, Interleukin
  • Receptors, Interleukin-7
  • Recombinant Fusion Proteins
  • Phosphotyrosine
  • Tyrosine
  • Glutathione Transferase
  • Phosphatidylinositol 3-Kinases
  • Phosphotransferases (Alcohol Group Acceptor)