INTERLEUKIN-13 SIGNAL-TRANSDUCTION IN LYMPHOHEMATOPOIETIC CELLS - SIMILARITIES AND DIFFERENCES IN SIGNAL-TRANSDUCTION WITH INTERLEUKIN-4 AND INSULIN

Interleukin-13 (IL-13) and interleukin-4 (IL-4) are related in structu re and function and are thought to share a common receptor component. We have investigated the signal transduction pathways activated by the se two growth factors, as well as insulin, in cell-lines and primary c ells of lymphohemopoietic origin. All three factors induced the tyrosi ne phosphorylation of a protein of 170 kDa (p170), which coimmunopreci pitated with the p85 subunit of PI3'-kinase, via high affinity interac tions mediated by the SH2 domains of p85. Antibodies raised against th e entire insulin-receptor substrate-1 (IRS-1) protein immunoprecipitat ed p170 much less efficiently than they did IRS-1 from 3T3 cells. Howe ver, antibodies directed against the conserved pleckstrin homology dom ain of IRS-1 immunoprecipitated both p170 and IRS-1 with similar effic iency, suggesting they share structural similarities in this region. I n lymphohemopoietic cells, IL-13, IL-4, and insulin failed to induce i ncreased tyrosine phosphorylation of Shc, or its association with grb2 , modification of Sos1, or activation of erk-1 and erk-2 mitogen-activ ated protein kinases, suggesting that p170 mediates downstream pathway s distinct from those mediated by IRS-1. Both IL-13 and IL-4 induced l ow levels of tyrosine phosphorylation of Tyk-2 and Jak-1. IL-4 also ac tivated the Jak-3-kinase, but, despite other similarities, IL-13 did n ot. Insulin failed to activate any of the known members of the Janus f amily of kinases. In that Jak-3 is reported to associate with the IL-2 gamma c chain, these data suggest that the IL-13 receptor does not ut ilize this subunit. However, both IL-13 and IL-4 induced tyrosine phos phorylation of the IL-4-140 kDa receptor chain, suggesting that this i s a component of both receptors in these cells and accounts for the si milarities in signaling pathways shared by IL-13 and IL-4.