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J. Biol. Chem., Vol. 280, Issue 13, 12747-12757, April 1, 2005

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Modulation of the Interleukin-6 Receptor Subunit Glycoprotein 130 Complex and Its Signaling by LMO4 Interaction^*

Veronica Novotny-Diermayr, Baohong Lin, Lei Gu, and Xinmin Cao

From the Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research of Singapore, Singapore, 138673

The interleukin (IL)-6-type cytokines play major roles in a variety of biological processes by signaling through a common receptor subunit, glycoprotein (gp) 130. We performed yeast two-hybrid screening to identify new binding partners of the activated gp130 and the associated Janus kinases. LMO4, a LIM domain-containing protein that belongs to a family of oncogenes, was identified in this assay. Further studies show that LMO4 associates with gp130 and Janus kinase1 in several mammalian cell types. It also interacts with protein-tyrosine phosphatase 2 (SHP2) and suppressor of cytokine signaling 3 (SOCS3). The binding domains involved in these interactions were mapped, and the interactions were shown to be in a direct manner by in vitro binding assays. It is likely that LMO4 exists in the gp130 complex. The cellular localization of LMO4 was detected primarily in the nucleus with a substantial amount also detected in the cytoplasm in several cell types. The effect of LMO4 in IL-6 signaling was subsequently examined. Overexpression of LMO4 enhanced the transcriptional activity and target gene expression of Stat 3 (signal transducers and activators of transcription 3). Consistent with this, silencing LMO4 expression in stable cell lines expressing the small interfering RNA of LMO4 decreased Stat3 activity. Furthermore, the half-life of gp130 was shortened, and the production of acute phase proteins induced by IL-6 was reduced. Together, our data reveal a positive regulatory role of LMO4 in IL-6 signaling, possibly by acting as a scaffold for stabilization of the gp130 complex. These studies may open up a link between the oncogenic effect of LMO proteins and their regulatory role in cytokine signaling in general.

Received for publication, November 8, 2004

^* This work was supported by the Agency for Science, Technology, and Research of Singapore. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Adjunct staff in the Department of Biochemistry, National University of Singapore. To whom correspondence should be addressed: Institute of Molecular and Cell Biology, Proteos Bldg., 61 Biopolis Dr., Singapore 138673. Tel.: 65-6586-9657; Fax: 65-6779-1117; E-mail: mcbcaoxm{at}imcb.a-star.edu.sg.

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