STAT3 Activation by Cytokines Utilizing gp130 and Related Transducers Involves a Secondary Modification Requiring an H7-Sensitive Kinase

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 92; no. 15; pp. 6915 - 6919
• Main Authors: Boulton, Teri G., Zhong Zhong, Wen, Zilong, Darnell, James E., Stahl, Neil, Yancopoulos, George D.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences of the United States of America 18-07-1995; National Acad Sciences
• Subjects: 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine; Antibodies; Antigens, CD; Base Sequence; Biological Transport; Cell Compartmentation; Cell lines; Cell Nucleus - metabolism; Cellular immunity; Cytokine Receptor gp130; Cytokines; Cytokines - pharmacology; DNA; DNA-Binding Proteins - metabolism; HeLa Cells; Hep G2 cells; Humans; Isoquinolines - pharmacology; Membrane Glycoproteins - metabolism; Molecular Sequence Data; Phosphorylation; Piperazines - pharmacology; Protein-Serine-Threonine Kinases - antagonists & inhibitors; Protein-Serine-Threonine Kinases - metabolism; Receptors; Signal Transduction; STAT1 Transcription Factor; STAT3 Transcription Factor; Trans-Activators - metabolism; Transducers
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.92.15.6915

Ciliary neurotrophic factor, oncostatin M, leukemiainhibitory factor, and interleukin 6 are related cytokines that initiate signaling by homodimerizing the signal-transducing receptor component gp130 or by heterodimerizing gp130 with a gp130-related receptor component. Receptor dimerization in turn activates receptor-associated kinases of the Jak/Tyk family, resulting in the rapid tyrosine phosphorylation of several intracellular proteins, including those of two members of the signal transducers and activators of transcription (STAT) family-STAT1 and STAT3. Here we show that all cytokines that utilize gp130 sequentially induce two distinct forms of STAT3 in all responding cells examined, with the two forms apparently differing because of a time-dependent secondary serine/threonine phosphorylation involving an H7-sensitive kinase. While both STAT3 forms bind DNA and translocate to the nucleus, the striking time-dependent progression from one form to the other implies other important functional differences between the two forms. Granulocyte colony-stimulating factor, which utilizes a receptor highly related to gp130, also induces these two forms of STAT3. In contrast to a number of other cytokines and growth factors, all cytokines using gp130 and related signal transducers consistently and preferentially induce the two forms of STAT3 as compared with STAT1; this characteristic STAT activation pattern is seen regardless of which Jak/Tyk kinases are used in a particular response, consistent with the notion that the receptor components themselves are the primary determinants of which STATs are activated.