CUEDC2 (CUE domain-containing 2) and SOCS3 (suppressors of cytokine signaling 3) cooperate to negatively regulate Janus kinase 1/signal transducers and activators of transcription 3 signaling.

Abstract

Janus kinase 1/signal transducers and activators of transcription 3 (JAK1/STAT3) pathway is one of the recognized oncogenic signaling pathways that frequently overactivated in a variety of human tumors. Despite rapid progress in elucidating the molecular mechanisms of activation of JAK/STAT pathway, the processes that regulate JAK/STAT deactivation need to be further clarified. Here we demonstrate that CUE domain-containing 2 (CUEDC2) inhibits cytokine-induced phosphorylation of JAK1 and STAT3 and the subsequent STAT3 transcriptional activity. Further analysis by a yeast two-hybrid assay showed that CUEDC2 could engage in a specific interaction with a key JAK/STAT inhibitor, SOCS3 (suppressors of cytokine signaling 3). The interaction between CUEDC2 and SOCS3 is required for the inhibitory effect of CUEDC2 on JAK1 and STAT3 activity. Additionally, we found CUEDC2 functions collaboratively with SOCS3 to inhibit JAK1/STAT3 signaling by increasing SOCS3 stability via enhancing its association with Elongin C. Therefore, our findings revealed a new biological activity for CUEDC2 as the regulator of JAK1/STAT3 signaling and paved the way to a better understanding of the mechanisms by which SOCS3 has been linked to suppression of the JAK/STAT pathway.

• Authors: Wei-Na Zhang, Li Wang, Qiong Wang, Xue Luo, Di-Feng Fang, Yuan Chen, Xin Pan, Jiang-Hong Man, Qing Xia, Bao-Feng Jin, Wei-Hua Li, Tao Li, Bing Liang, Liang Chen, Wei-Li Gong, Ming Yu, Ai-Ling Li, Tao Zhou, Hui-Yan Li
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 287 Issue 1 Pg. 382-392 (Jan 02 2012) ISSN: 1083-351X [Electronic] United States
• PMID: 22084247 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• CUEDC2 protein, human
• Carrier Proteins
• ELOC protein, human
• Elongin
• Membrane Proteins
• SOCS3 protein, human
• STAT3 Transcription Factor
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins
• Transcription Factors
• Janus Kinase 1

Topics

• Adaptor Proteins, Signal Transducing
• Carrier Proteins (metabolism)
• Cell Line
• Elongin
• Enzyme Activation
• Humans
• Janus Kinase 1 (metabolism)
• Membrane Proteins (metabolism)
• Phosphorylation
• Protein Stability
• Proteolysis
• STAT3 Transcription Factor (metabolism)
• Signal Transduction
• Suppressor of Cytokine Signaling 3 Protein
• Suppressor of Cytokine Signaling Proteins (metabolism)
• Transcription Factors (metabolism)
• Transcription, Genetic