Shc Mediates IL-6 Signaling by Interacting with gp130 and Jak2 Kinase

Vincenzo Giordano, Giulia De Falco, Rita Chiari, Ileana Quinto, Pier Giuseppe Pelicci, Linda Bartholomew, Paola Delmastro, Massimo Gadina, Giuseppe Scala

Research output: Contribution to journalArticlepeer-review

Abstract

IL-6 is a multifunctional cytokine involved in hemopoiesis, immune regulation, inflammation, neural development, and infection. IL-6 belongs to a family of related cytokines that includes leukemia inhibitory factor, oncostatin M, IL-11, ciliary neurotropic factor, and cardiotropin-1, all of which initiate signaling through a receptor-associated gp130. IL-6 induces homodimerization of gp130 and activates the Jak/STAT pathway of signal transduction. In addition, IL-6 stimulates the mitogen-activated protein kinases designated ERK (extracellular signal-regulated kinase)-1 and -2. Activation of ERK-1 and -2 may involve the Src homology-2 containing proteins Shc and Grb2. Here we provide evidence that Shc could function as signaling molecules for IL-6 in DeFew-IL-6R/gp130 cells, a human B lymphoma cell line engineered to express high levels of both the IL-6R (p80) and the gp130 subunit. IL-6 was shown to promote the rapid tyrosine phosphorylation of gp130, Jak2, and Shc proteins. Moreover, Shc associated both in vivo and in vitro with phosphorylated gp130 through the Shc-Src homology-2 domain. We also report that Shc bound to activated Jak2 by using the Shc amino terminal phosphotyrosine interaction domain. Following IL-6 stimulation, Shc physically associated with Grb2. Thus, the data point to Shc proteins as a functional link between the Jak2 and Ras pathways of IL-6 signal transduction.

Original languageEnglish
Pages (from-to)4097-4103
Number of pages7
JournalJournal of Immunology
Volume158
Issue number9
Publication statusPublished - May 1 1997

ASJC Scopus subject areas

  • Immunology

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