期刊
CELLULAR SIGNALLING
卷 39, 期 -, 页码 9-17出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.cellsig.2017.07.014
关键词
ACK1; HSP90; Lung cancer; SIAH2; STAT1; STAT3
类别
资金
- Wilhelm Sander-Stiftung [2010.078]
- Deutsche Forschungsgemeinschaft [KR2291/4-1, KR2291/5-1, KR2291/7-1]
- Deutsche Krebshilfe [110909, 110125]
- University Medical Center Mainz and Naturwissenschaftlich-medizinisches Forschungszentrum Main
- NMFZ
- Austrian Science Fund [FWF-P 26011, FWF-P 29251-B28]
- European Training Network (MSCA-ITN-ETN ALKATRAS) [675712]
- Marie Curie Actions (MSCA) [675712] Funding Source: Marie Curie Actions (MSCA)
Signal transducers and activators of transcription (STATs) are latent, cytoplasmic transcription factors. Janus kinases (JAKs) and activated CDC42-associated kinase-1 (ACK1/TNK2) catalyse the phosphorylation of STAT1 and the expression of its target genes. Here we demonstrate that catalytically active ACK1 promotes the phosphorylation and nuclear accumulation of STAT1 in transformed kidney cells. These processes are associated with STAT1-dependent gene expression and an interaction between endogenous STAT? and ACK1. Moreover, the E3 ubiquitin ligase seven-in-absentia homolog-2 (SIAH2), which targets ACK1 through valine-909 for proteasomal degradation, attenuates the ACK1-STAT1 signalling node. We further show that ACK1 promotes the phosphorylation and nuclear accumulation of STAT3 in cultured cells and that the levels of ACK1 correlate positively with the levels of tyrosine phosphorylated STAT3 in primary lung adenocarcinoma (ADC) cells. Global analysis of ACK1 interaction partners validated the interaction of ACK1 with heat shock protein 90 (HSP90 alpha/beta). Inhibition of this chaperone with the novel drug Onalespib (AT13387) demonstrates that HSP90 is an upstream regulator of the ACK1-dependent phosphorylation of STAT? and STAT3. In addition to these molecular insights, our data offer a pharmacological strategy to control the ACK1-STAT signalling axis.
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