Signaling through a Novel Domain of gp130 Mediates Cell Proliferation and Activation of Hck and Erk Kinases

Abstract

Interleukin-6 (IL-6) induces the activation of the Src family kinase Hck, which is associated with the IL-6 receptor β-chain, gp130. Here we describe the identification of an “acidic” domain comprising amino acids 771 to 811 of gp130 as a binding region for Hck, which mediates proliferative signaling. The deletion of this region of gp130 (i.e., in deletion mutant d771-811) resulted in a significant reduction of Hck kinase activity and cell proliferation upon stimulation of gp130 compared to wild-type gp130. In addition, d771-811 disrupted the growth factor-stimulated activation of Erk and the dephosphorylation of Pyk2. Based on these findings, we propose a novel, acidic domain of gp130, which is responsible for the activation of Hck, Erk, and Pyk2 and signals cell proliferation upon growth factor stimulation.

ACKNOWLEDGMENTS

We thank Susanne Anton for excellent technical assistance, Friedemann Horn (Leipzig, Germany) for providing the EpoR-gp130 chimera cDNA, and Mark Showers (Boston, Mass.) for providing Baf-B03 cells.

This work was supported by grants of the Deutsche Krebshilfe 10-1094-HA and 10-1678-HA2 (to M.H.).