Interleukin-4 proliferative signal transduction involves the activation of a tyrosine-specific phosphatase and the dephosphorylation of an 80-kDa protein.
Interleukin-4 (IL-4) is a cytokine that expresses its biological effects by binding to specific membrane receptors. Although the diverse biological properties of this molecule have been characterized extensively the biochemical mechanisms by which extracellular binding events lead to biological responses remain unclear. IL-4 can stimulate the proliferation of several hemopoietic cell types, and we have taken advantage of its ability to induce the growth of leukemic cell lines to investigate the role that protein phosphorylation events might play in IL-4 mitogenic signal transduction. We show that the addition of IL-4 to several leukemic cell lines of different origin causes the rapid dephosphorylation of an 80-kDa phosphoprotein (p80) from tyrosine residues. This event occurs in a dose-responsive manner closely correlating to that of biological activity, and both are blocked by an anti-IL-4-specific antiserum. The ability of sodium orthovanadate to prevent IL-4-induced dephosphorylation of p80 suggests that this event is mediated by a protein-tyrosine-phosphatase (EC 3.1.3.48). The importance of the role that tyrosine-specific dephosphorylation plays in mediating IL-4 mitogenic signal transduction is substantiated by the ability of sodium orthovanadate in cell culture to block effectively IL-4-induced proliferation at doses that enhance the proliferation stimulated by either granulocyte-macrophage colony-stimulating factor or interleukin-3.
Mire-Sluis
A R
AR
Division of Immunobiology, National Institute for Biological Standards and Control, Potters Bar, Hertfordshire, United Kingdom.
Thorpe
R
R
D000255:Adenosine Triphosphate / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004591:Electrophoresis, Polyacrylamide Gel; D004789:Enzyme Activation; D019833:Genistein; D006801:Humans; D015847:Interleukin-4 / Q000378:metabolism*; D007529:Isoflavones / Q000494:pharmacology; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D015398:Signal Transduction; D014638:Vanadates / Q000494:pharmacology
D007529:Isoflavones; D010750:Phosphoproteins; D011994:Recombinant Proteins; D015847:Interleukin-4; D014638:Vanadates; D000255:Adenosine Triphosphate; D019833:Genistein; D017027:Protein Tyrosine Phosphatases