title: 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.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China.
authors.forename: Xiuting
authors.initials: X
authors.lastname: Chen
authors.forename: Zhe
authors.initials: Z
authors.lastname: Ying
authors.forename: Xi
authors.initials: X
authors.lastname: Lin
authors.forename: Huanxin
authors.initials: H
authors.lastname: Lin
authors.forename: Jueheng
authors.initials: J
authors.lastname: Wu
authors.forename: Mengfeng
authors.initials: M
authors.lastname: Li
authors.forename: Libing
authors.initials: L
authors.lastname: Song
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology*; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism; D004938:Esophageal Neoplasms / Q000201:enzymology*; D055785:Gene Knockdown Techniques; D006801:Humans; D053614:Janus Kinase 2 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000201:enzymology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism*; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D025941:Protein Interaction Mapping; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D018874:Spheroids, Cellular
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C492429:AGK protein, human; D017853:Phosphotransferases (Alcohol Group Acceptor); C507924:JAK2 protein, human; D053614:Janus Kinase 2