title: STAT3 mutations correlated with hyper-IgE syndrome lead to blockage of IL-6/STAT3 signalling pathway.
abstract: Of all the causes identified for the disease hyper-immunoglobulinemia E syndrome (HIES), a homozygous  mutation in tyrosine kinase2 (TYK2) and heterozygous mutations in STAT3 are implicated the defects in Jak/STAT signalling pathway in the pathogenesis of HIES. Mutations of STAT3 have been frequently clinically identified in autosomaldominant (AD) HIES patients' cells, and therefore, the genotype of STAT3 has been associated with the phenotype of HIES. Here, we conducted studies on the functional loss of the seven specific STAT3 mutations correlated with ADHIES. Using STAT3-null human colon carcinoma cell line A4 cells, we generated seven mutants of STAT3 bearing single mutations  clinically identified in AD-HIES patients' cells and studied the functional loss of these mutants in IL- 6-Jak/STAT3 signalling pathway. Our results show that five STAT3 mutants bearing mutations in the DNA-binding domain maintain the phosphorylation of Tyr705 and the ability of dimerization while the other two with mutations in SH2 domain are devoid of the phosphorylation of Try705 and abrogate the dimerization in response to IL-6. The phosphorylation of Ser727 in these mutants shows diversity in response to IL-6. These mutations eventually converge on the abnormalities of the IL-6/Gp130/Jak2-mediated STAT3 transactivation on target genes, indicative of the dysregulation of JAK/STAT signalling present in HIES.
authors.affiliation: School of Life Science, Lanzhou University, Lanzhou, Gansu 730000, People's Republic of China.
authors.forename: Jianxin
authors.initials: J
authors.lastname: He
authors.forename: Jie
authors.initials: J
authors.lastname: Shi
authors.forename: Ximing
authors.initials: X
authors.lastname: Xu
authors.forename: Wenhua
authors.initials: W
authors.lastname: Zhang
authors.forename: Yuxin
authors.initials: Y
authors.lastname: Wang
authors.forename: Xing
authors.initials: X
authors.lastname: Chen
authors.forename: Yuping
authors.initials: Y
authors.lastname: Du
authors.forename: Ning
authors.initials: N
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Qin
authors.initials: Q
authors.lastname: Wang
authors.forename: Jinbo
authors.initials: J
authors.lastname: Yang
mesh_terms: D045744:Cell Line, Tumor; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D006579:Heterozygote; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism*; D007589:Job Syndrome / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D008958:Models, Molecular; D009154:Mutation; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D014162:Transfection; D018909:src Homology Domains
chemical_list: D015850:Interleukin-6; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D004247:DNA