Previous studies suggested that interleukin-11 (IL-11) induces the activation of mitogen-activated protein kinase (MAPK) in mouse 3T3L1 cells. However, the mechanisms by which IL-11 activates MAPK remain elusive. Our present results show that IL-11 promotes the formation of the active GTP-bound form of Ras, suggesting that IL-11 actions may be transduced in part through the Ras/MAPK signaling pathway. By immunoblotting and immunoprecipitation, we further demonstrate the association of tyrosine phosphoproteins with Grb2, an adaptor protein serving as a key intermediate for Ras activation. These phosphotyrosine-containing proteins have been subsequently identified to be JAK2, Fyn, and Syp. JAK2 and Fyn are transiently associated with Grb2 upon stimulation with IL-11, suggesting that JAK2 and Fyn may be involved in transducing signals from the IL-11 receptorglycoprotein 130 to the Ras system through Grb2. Taken together, these results suggest that IL-11-induced interactions of JAK2, Fyn, and Grb2 may not only provide a novel mechanism for the activation of the Ras/MAPK system but also indicate cross-talk among diverse signaling pathways.

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