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Type of publication: Journal Article
Type of document: Full Paper

Year: 2017

Authors: Mahendrarajah, N; Borisova, ME; Reichardt, S; Godmann, M; Sellmer, A; Mahboobi, S; Haitel, A; Schmid, K; Kenner, L; Heinzel, T; Beli, P; Krämer, OH

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

Source: Cell Signal. 2017; 39:9-17

Authors Vetmeduni Vienna:

Kenner Lukas

Vetmed Research Units
Institute of Pathology, Pathology of Laboratory Animals

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 STAT1 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 (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 STAT1 and STAT3. In addition to these molecular insights, our data offer a pharmacological strategy to control the ACK1-STAT signalling axis.Copyright © 2017 Elsevier Inc. All rights reserved.

Keywords Pubmed: Benzamidespharmacology
HEK293 Cells
HSP90 Heat-Shock Proteinsmetabolism
Nuclear Proteinsgeneticsmetabolism
Protein-Tyrosine Kinasesgeneticsmetabolism
STAT1 Transcription Factorgeneticsmetabolism
STAT3 Transcription Factorgeneticsmetabolism
Tumor Cells, Cultured
Ubiquitin-Protein Ligasesgeneticsmetabolism

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