STAT3Activation In Response To IL-6is Prolonged By The Binding Of IL-6R To EGFR

The STAT transcription factors, and especially STAT3, play vital roles in tumor initiation and progression. Aberrant activation of STAT3leads to the over expression of oncogenes that drive proliferation and metastasis, and inhibit apoptosis. Following ligand-induced dimerization of the interleukin-6receptor (IL-6R), the associated kinases JAK1and JAK2cross-phosphorylate tyrosine residues of adjacent gp130subunits of the complex. The SH2domain of STAT3binds to newly phosphorylated tyrosines, followed by the phosphorylation of Y705of STAT3. Two phosphorylated STAT3monomers then dimerize and translocate to the nucleus, where they activate the transcription of many downstream genes. The activation of STAT3by tyrosine phosphorylation, essential for normal development and for a normal inflammatory response to invading pathogens, is kept in check by negative regulators. Suppressor of cytokine signaling3(SOCS3), the major negative regulator of IL-6-dependent signaling, is highly induced by activated STAT3, strongly inhibiting further STAT3phosphorylation and thus collaborating with additional negative regulatory mechanisms to prevent excessive activation of potentially deleterious gene expression. Abnormal constitutive activation of STAT3, which contributes to the pathology of cancer and to chronic inflammatory diseases such as rheumatoid arthritis, occurs when negative regulation is not fully effective.As an activator of the JAK-STAT signaling pathway, IL-6can act in both a pro-inflammatory and anti-inflammatory manner. Deregulation of IL-6production can cause severe disease, such as rheumatoid arthritis, psoriasis, arteriosclerosis and cancer. Through the JAK/STAT signaling pathway, IL-6mediates the production of IL-17and IL-10while regulating TH17, which is important in auto-immunity. IL-6elevation and the chronic inflammation that follows are pro-tumorigenic. IL-6exerts powerful anti-apoptotic functions through the induction of BCL-2, BCL-xL, and related inhibitors. Therefore, anti-IL-6/IL-6R monoclonal antibodies are used to inhibit aberrant and prolonged IL-6signaling in the treatment of autoimmunity and cancer.The epidermal growth factor receptor (EGFR) is well known to catalyze the tyrosine phosphorylation of STAT3in response to EGF, and the intrinsic kinase activity of the receptor, but not any of the JAKs, is required for this reaction. Upon activation by EGF, the EGFR dimerizes to facilitate cross-phosphorylation of several tyrosine residues, including Y1068, the binding site for STAT3. Multiple tyrosine phosphorylations of EGFR initiate downstream signaling cascades that facilitate proliferation, regeneration and tumorigenesis. Since EGFR activation can mediate both IL-6production and STAT3activation, we investigated the role of EGFR in regulating STAT3activation in response to IL-6.As the major negative regulator of STAT3, SOCS3,is induced by tyrosine-phosphorylated STAT3and terminates STAT3phosphorylation about2h after initial exposure of cells to members of the interleukin-6(IL-6) family of cytokines, by binding cooperatively to the common receptor subunit gp130and JAKs1and2. We show here that, when the epidermal growth factor receptor (EGFR) is present and active, STAT3is re-phosphorylated about4h after exposure of cells to IL-6or oncostatin M (OSM) and remains active for many hours. Newly synthesized IL-6drives association of the IL-6receptor and gp130with EGFR, leading to EGFR-dependent re-phosphorylation of STAT3, which is not inhibited by the continued presence of SOCS3. This second wave of STAT3activation supports sustained expression of a subset of IL-6-induced proteins, several of which play important roles in inflammation and cancer, where both IL-6secretion and EGFR levels are often elevated.