Regulation of STAT3 by direct binding to the Rac1 GTPase.

The signal transducers and activators of transcription (STAT) transcription factors become phosphorylated on tyrosine and translocate to the nucleus after stimulation of cells with growth factors or cytokines. We show that the Rac1 guanosine triphosphatase can bind to and regulate STAT3 activity. Dominant negative Rac1 inhibited STAT3 activation by growth factors, whereas activated Rac1 stimulated STAT3 phosphorylation on both tyrosine and serine residues. Moreover, activated Rac1 formed a complex with STAT3 in mammalian cells. Yeast two-hybrid analysis indicated that STAT3 binds directly to active but not inactive Rac1 and that the interaction occurs via the effector domain. Rac1 may serve as an alternate mechanism for targeting STAT3 to tyrosine kinase signaling complexes.

[1]  J. Turkson,et al.  Activation of Stat3 in v-Src-transformed Fibroblasts Requires Cooperation of Jak1 Kinase Activity* , 2000, The Journal of Biological Chemistry.

[2]  R. Jove,et al.  Activation of Stat3 preassembled with platelet-derived growth factor β receptors requires Src kinase activity , 2000, Oncogene.

[3]  J. Abe,et al.  Fyn and JAK2 Mediate Ras Activation by Reactive Oxygen Species* , 1999, The Journal of Biological Chemistry.

[4]  M. Vignais,et al.  Distinct Mechanisms of Activation of Stat1 and Stat3 by Platelet-Derived Growth Factor Receptor in a Cell-Free System , 1999, Molecular and Cellular Biology.

[5]  B. Babior.  NADPH oxidase: an update. , 1999, Blood.

[6]  Channing J Der,et al.  Rho family proteins and Ras transformation: the RHOad less traveled gets congested , 1998, Oncogene.

[7]  J. Darnell.  STATs and gene regulation. , 1997, Science.

[8]  I. Kerr,et al.  Activation of Jak2 catalytic activity requires phosphorylation of Y1007 in the kinase activation loop , 1997, Molecular and cellular biology.

[9]  C. Der,et al.  Dbl family proteins. , 1997, Biochimica et biophysica acta.

[10]  J. Chant,et al.  Rac and Cdc42 Induce Actin Polymerization and G1 Cell Cycle Progression Independently of p65PAK and the JNK/SAPK MAP Kinase Cascade , 1996, Cell.

[11]  V. Ferrans,et al.  Regulation of reactive-oxygen-species generation in fibroblasts by Rac1. , 1996, The Biochemical journal.

[12]  Alan Wells,et al.  STAT Activation by Epidermal Growth Factor (EGF) and Amphiregulin , 1996, The Journal of Biological Chemistry.

[13]  M. Vignais,et al.  Platelet-derived growth factor induces phosphorylation of multiple JAK family kinases and STAT proteins , 1996, Molecular and cellular biology.

[14]  D. Levy,et al.  Roles of JAKs in activation of STATs and stimulation of c-fos gene expression by epidermal growth factor , 1996, Molecular and cellular biology.

[15]  J. Chernoff,et al.  Identification of a Mouse p21Cdc42/Rac Activated Kinase (*) , 1995, The Journal of Biological Chemistry.

[16]  J. Darnell,et al.  Choice of STATs and other substrates specified by modular tyrosine-based motifs in cytokine receptors , 1995, Science.

[17]  J. Darnell,et al.  Contribution of STAT SH2 groups to specific interferon signaling by the Jak-STAT pathway , 1995, Science.

[18]  John G. Collard,et al.  Identification of an invasion-inducing gene, Tiam-1, that encodes a protein with homology to GDP-GTP exchangers for Rho-like proteins , 1994, Cell.

[19]  O. Silvennoinen,et al.  Signaling by the cytokine receptor superfamily: JAKs and STATs. , 1994, Trends in biochemical sciences.

[20]  J. Darnell,et al.  Stat3: a STAT family member activated by tyrosine phosphorylation in response to epidermal growth factor and interleukin-6. , 1994, Science.

[21]  J. Darnell,et al.  Interferon activation of the transcription factor Stat91 involves dimerization through SH2-phosphotyrosyl peptide interactions , 1994, Cell.

[22]  J. Yodoi,et al.  Redox regulation of a src family protein tyrosine kinase p56lck in T cells. , 1993, Oncogene.

[23]  J. Darnell,et al.  A common nuclear signal transduction pathway activated by growth factor and cytokine receptors. , 1993, Science.

[24]  Jonathan A. Cooper,et al.  Mammalian Ras interacts directly with the serine/threonine kinase raf , 1993, Cell.

[25]  B. Cochran,et al.  The SIF binding element confers sis/PDGF inducibility onto the c‐fos promoter. , 1990, The EMBO journal.

[26]  B. Cochran,et al.  Inducible binding of a factor to the c-fos regulatory region. , 1987, Proceedings of the National Academy of Sciences of the United States of America.