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.
Simon
A R
AR
Pulmonary and Critical Care Division, Tupper Research Institute, New England Medical Center, Boston, MA 02111, USA.
Vikis
H G
HG
Stewart
S
S
Fanburg
B L
BL
Cochran
B H
BH
Guan
K L
KL
D019943:Amino Acid Substitution; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002522:Chlorocebus aethiops; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004789:Enzyme Activation; D004815:Epidermal Growth Factor / Q000494:pharmacology; D005786:Gene Expression Regulation; D017930:Genes, Reporter; D005822:Genetic Vectors; D020662:Guanine Nucleotide Exchange Factors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D053614:Janus Kinase 2; D009154:Mutation; D009363:Neoplasm Proteins; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D019000:Phosphotyrosine / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D011518:Proto-Oncogene Proteins; D051381:Rats; D050796:STAT3 Transcription Factor; D015398:Signal Transduction; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D020798:Two-Hybrid System Techniques; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism*
D004268:DNA-Binding Proteins; D020662:Guanine Nucleotide Exchange Factors; D009363:Neoplasm Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C494088:Stat3 protein, rat; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C087334:TIAM1 protein, human; C513259:Tiam1 protein, rat; D015534:Trans-Activators; D010768:Phosphoserine; D019000:Phosphotyrosine; D004815:Epidermal Growth Factor; D011505:Protein-Tyrosine Kinases; C507924:JAK2 protein, human; C507927:Jak2 protein, rat; D053614:Janus Kinase 2; D020830:rac1 GTP-Binding Protein