STAT3 activation in response to IL-6 is prolonged by the binding of IL-6 receptor to EGF receptor

Y Wang, AHH van Boxel-Dezaire… - Proceedings of the …, 2013 - National Acad Sciences
Proceedings of the National Academy of Sciences, 2013National Acad Sciences
The activation of STAT3 by tyrosine phosphorylation, essential for normal development and
for a normal inflammatory response to invading pathogens, is kept in check by negative
regulators. 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. SOCS3, the major negative regulator of STAT3, is
induced by tyrosine-phosphorylated STAT3 and terminates STAT3 phosphorylation about 2 …
The activation of STAT3 by tyrosine phosphorylation, essential for normal development and for a normal inflammatory response to invading pathogens, is kept in check by negative regulators. 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. SOCS3, the major negative regulator of STAT3, is induced by tyrosine-phosphorylated STAT3 and terminates STAT3 phosphorylation about 2 h after initial exposure of cells to members of the IL-6 family of cytokines by binding cooperatively to the common receptor subunit gp130 and JAKs 1 and 2. We show here that when the epidermal growth factor receptor (EGFR) is present and active, STAT3 is rephosphorylated about 4 h after exposure of cells to IL-6 or oncostatin M and remains active for many hours. Newly synthesized IL-6 drives association of the IL-6 receptor and gp130 with EGFR, leading to EGFR-dependent rephosphorylation of STAT3, which is not inhibited by the continued presence of SOCS3. This second wave of STAT3 activation supports sustained expression of a subset of IL-6-induced proteins, several of which play important roles in inflammation and cancer, in which both IL-6 secretion and EGFR levels are often elevated.
National Acad Sciences