ABSTRACT
Signal transducer and activator of transcription 3 (STAT3) is involved in cell proliferation, differentiation, and cell survival during immune responses, hematopoiesis, neurogenesis, and other biological processes. STAT3 activity is regulated by a variety of mechanisms, including phosphorylation and nuclear translocation. To clarify the molecular mechanisms underlying the regulation of STAT3 activity, we performed yeast two-hybrid screening. We identified ARL3 (ADP-ribosylation factor-like 3) as a novel STAT3-binding partner. ARL3 recognizes the DNA-binding domain as well as the C-terminal region of STAT3 in vivo, and their binding was the strongest when both proteins were activated. Importantly, small interfering RNA-mediated reduction of endogenous ARL3 expression decreased IL-6-induced tyrosine phosphorylation, nuclear accumulation, and transcriptional activity of STAT3. These results indicate that ARL3 interacts with STAT3 and regulates the transcriptional activation of STAT3 by influencing its nuclear accumulation of STAT3.
Subject(s)
ADP-Ribosylation Factors/metabolism , Cell Nucleus/metabolism , STAT3 Transcription Factor/metabolism , ADP-Ribosylation Factors/genetics , Active Transport, Cell Nucleus/drug effects , Active Transport, Cell Nucleus/genetics , Cell Nucleus/genetics , Gene Expression Regulation/drug effects , HeLa Cells , Humans , Interleukin-6/pharmacology , Phosphorylation/drug effects , Phosphorylation/genetics , Protein Binding/drug effects , Protein Binding/genetics , STAT3 Transcription Factor/geneticsABSTRACT
Signal transducers and activators of transcription (STATs) mediate cell proliferation, differentiation and survival in immune responses, hematopoiesis, neurogenesis and other biological processes. STAT3, for example, is involved in the epithelial-mesenchymal transition during gastrulation, organogenesis, wound healing and cancer progression. STAT activity is regulated by a variety of mechanisms, including nuclear translocation. To clarify the molecular mechanisms underlying the regulation of STAT activity, we performed yeast two-hybrid screening. Here, we identified binder of ADP-ribosylation factor-like two (BART) as a novel STAT-binding partner. Importantly, we showed that BART is essential for the transcriptional activity and nuclear retention of STAT3. Furthermore, an effector of BART, ADP-ribosylation factor-like 2 (ARL2) was also involved in nuclear retention of STAT3. These results indicate that BART plays an essential role in the nuclear retention of STAT3 through interaction with ARL2.
