Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase.
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.
Mesh Terms:
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Antigens, CD, Cytokine Receptor gp130, DNA-Binding Proteins, GRB2 Adaptor Protein, Humans, Interleukin-6, Janus Kinase 2, Membrane Glycoproteins, Phosphorylation, Phosphotyrosine, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Receptors, Interleukin, Receptors, Interleukin-6, STAT3 Transcription Factor, Shc Signaling Adaptor Proteins, Signal Transduction, Trans-Activators, src Homology Domains
Adaptor Proteins, Signal Transducing, Adaptor Proteins, Vesicular Transport, Antigens, CD, Cytokine Receptor gp130, DNA-Binding Proteins, GRB2 Adaptor Protein, Humans, Interleukin-6, Janus Kinase 2, Membrane Glycoproteins, Phosphorylation, Phosphotyrosine, Protein-Tyrosine Kinases, Proteins, Proto-Oncogene Proteins, Receptors, Interleukin, Receptors, Interleukin-6, STAT3 Transcription Factor, Shc Signaling Adaptor Proteins, Signal Transduction, Trans-Activators, src Homology Domains
J. Immunol.
Date: May. 01, 1997
PubMed ID: 9126968
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