Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells
Xiuting Chen, … , Mengfeng Li, Libing Song
Xiuting Chen, … , Mengfeng Li, Libing Song
Published May 8, 2013
Citation Information: J Clin Invest. 2013;123(6):2576-2589. https://doi.org/10.1172/JCI68143.
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Research Article Oncology

Acylglycerol kinase augments JAK2/STAT3 signaling in esophageal squamous cells

Abstract

JAK2 activity is tightly controlled through a self-inhibitory effect via its JAK homology domain 2 (JH2), which restricts the strength and duration of JAK2/STAT3 signaling under physiological conditions. Although multiple mutations within JAK2, which abrogate the function of JH2 and sustain JAK2 activation, are widely observed in hematological malignancies, comparable mutations have not been detected in solid tumors. How solid tumor cells override the autoinhibitory effect of the JH2 domain to maintain constitutive activation of JAK2/STAT3 signaling remains puzzling. Herein, we demonstrate that AGK directly interacted with the JH2 domain to relieve inhibition of JAK2 and activate JAK2/STAT3 signaling. Overexpression of AGK sustained constitutive JAK2/STAT3 activation, consequently promoting the cancer stem cell population and augmenting the tumorigenicity of esophageal squamous cell carcinoma (ESCC) cells both in vivo and in vitro. Furthermore, AGK levels significantly correlated with increased STAT3 phosphorylation, poorer disease-free survival, and shorter overall survival in primary ESCC. More importantly, AGK expression was significantly correlated with JAK2/STAT3 hyperactivation in ESCC, as well as in lung and breast cancer. These findings uncover a mechanism for constitutive activation of JAK2/STAT3 signaling in solid tumors and may represent a prognostic biomarker and therapeutic target.

Authors

Xiuting Chen, Zhe Ying, Xi Lin, Huanxin Lin, Jueheng Wu, Mengfeng Li, Libing Song

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Figure 1

Identification of AGK as a JH2 domain–interacting protein that activates the JAK2/STAT3 pathway.

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Identification of AGK as a JH2 domain–interacting protein that activates...
(A) Lysates from ECa109 cells transfected with HA-JH2 were immunoprecipitated using anti-HA affinity agarose, followed by MS peptide sequencing. AGK was identified in the precipitate together with the 7 other indicated proteins. (B) Representative MS plots and sequences of peptides from AGK. (C) Immunoprecipitation assay revealing that AGK interacted with JAK2 and STAT3. (D) STAT3 luciferase reporter activity was analyzed in AGK-transduced, AGK-silenced, and control cells. Error bars represent the means ± SD of 3 independent experiments. *P < 0.05. (E) Western blot analysis of p-STAT3 (Tyr705), total STAT3, p-JAK2 (Tyr1007-1008), and total JAK2 expression in the indicated cells. α-Tubulin was used as a loading control. (F) GSEA plot showing that AGK expression positively correlated with STAT3-activated gene signatures (DAUER_STAT3_TARGETS_UP, V$STAT3_01/02) and inversely correlated with STAT3-suppressed gene signatures (DAUER_STAT3_TARGETS_Dn) in published ESCC patient gene expression profiles (NCBI/GEO/GSE20347 and GSE29001, n = 79). IP, immunoprecipitation.