Mahendrarajah, Nisintha and Borisova, Marina E. and Reichardt, Sigrid and Godmann, Maren and Sellmer, Andreas and Mahboobi, Siavosh and Haitel, Andrea and Schmid, Katharina and Kenner, Lukas and Heinzel, Thorsten and Beli, Petra and Kraemer, Oliver H. (2017) HSP90 is necessary for the ACK1-dependent phosphorylation of STAT1 and STAT3. CELLULAR SIGNALLING, 39. pp. 9-17. ISSN 0898-6568, 1873-3913
Full text not available from this repository. (Request a copy)Abstract
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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | CELL LUNG-CANCER; INHIBITOR; CARCINOMA; AT13387; ACK1; TUMORIGENESIS; EXPRESSION; KINASE1; BIOLOGY; ACK1; HSP90; Lung cancer; SIAH2; STAT1; STAT3 |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 14 Dec 2018 13:19 |
| Last Modified: | 19 Feb 2019 14:07 |
| URI: | https://pred.uni-regensburg.de/id/eprint/1944 |
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