HSP90 is necessary for the ACK1-dependent phosphorylation of STAT1 and STAT3.

Signal transducers and activators of transcription are latent, cytoplasmic transcription factors. Janus kinases (JAKs) and activated CDC42-associated kinase-1 (ACK1/TNK2) catalyse the phosphorylation of and the expression of its target genes. Here we demonstrate that catalytically active ACK1 promotes the phosphorylation and nuclear accumulation of duanyu18131 in transformed kidney cells. These processes are associated with gene expression and an interaction between endogenous duanyu18131 and ACK1. Moreover, the E3 ubiquitin ligase seven-in-absentia homolog-2 (SIAH2), which targets ACK1 through valine-909 for proteasomal degradation, attenuates the signalling node. We further show that ACK1 promotes the phosphorylation and nuclear accumulation of in cultured cells and that the levels of ACK1 correlate positively with the levels of tyrosine phosphorylated duanyu18133 in primary lung adenocarcinoma (ADC) cells. Global analysis of ACK1 interaction partners validated the interaction of ACK1 with heat shock protein 90 (HSP90α/β). Inhibition of this chaperone with the novel drug Onalespib (AT13387) demonstrates that HSP90 is an upstream regulator of the ACK1-dependent phosphorylation of duanyu18131 and In addition to these molecular insights, our data offer a pharmacological strategy to control the signalling axis.

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