Toxin-induced RhoA activity mediates CCL1-triggered signal transducers and activators of transcription protein signaling.
RhoA is reportedly involved in signal transducers and activators of transcription (STAT)-dependent transcription. However, the pathway connecting the GTPase and STAT signaling has not been characterized. Here, we made use of bacterial toxins, which directly activate Rho GTPases to analyze this pathway. Cytotoxic necrotizing factors (CNFs) are produced by pathogenic Escherichia coli strains and by Yersinia pseudotuberculosis. They activate small GTPases of the Rho family by deamidation of a glutamine, which is crucial for GTP hydrolysis. We show that RhoA activation leads to phosphorylation and activation of STAT3 and identify signal proteins involved in this pathway. RhoA-dependent STAT3 stimulation requires ROCK and Jun kinase activation as well as AP1-induced protein synthesis. The secretion of one or more factors activates the JAK-STAT pathway in an auto/paracrine manner. We identify CCL1/I-309 as an essential cytokine, which is produced and secreted upon RhoA activation and which is able to activate STAT3-dependent signaling pathways.
Institute for Experimental and Clinical Pharmacology and Toxicology, Albert-Ludwigs-University of Freiburg, Albert-Str. 25, 79104 Freiburg, Germany.
Simone
S
Reipschläger
Katharina
K
Kubatzky
Sanaz
S
Taromi
Meike
M
Burger
Joachim
J
Orth
Klaus
K
Aktories
Gudula
G
Schmidt
D001427:Bacterial Toxins / Q000494:pharmacology*; D054402:Chemokine CCL1 / Q000378:metabolism*; D004789:Enzyme Activation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D053612:Janus Kinases / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D001427:Bacterial Toxins; C065971:CCL1 protein, human; D054402:Chemokine CCL1; D050791:STAT Transcription Factors; D018808:Transcription Factor AP-1; D053612:Janus Kinases; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein