The Ying and Yang of STAT3 in Human Disease

Abstract

The transcription factor signal transducer and activator of transcription 3 (STAT3) is a critical regulator of multiple, diverse cellular processes. Heterozgyous, germline, loss-of-function mutations in STAT3 lead to the primary immune deficiency Hyper-IgE syndrome. Heterozygous, somatic, gain-of-function mutations in STAT3 have been reported in malignancy. Recently, germline, heterozygous mutations in STAT3 that confer a gain-of-function have been discovered and result in early-onset, multi-organ autoimmunity. This review summarizes what is known about the role of STAT3 in human disease.

STAT3 signaling in immunity

“…Recently, de novo activating point mutations in STAT3 (i.e., GOF) were identified in individuals with juvenile-onset autoimmunity and lymphoproliferation. Disease manifestations include type I diabetes in infancy, lymphadenopathy, autoimmune cytopenias, primary hypothyroidism, solid organ autoimmunity and short stature [77–80]. The STAT3 point mutations in these individuals affect conserved residues in the DNA binding, SH2 or transactivation domains, which are different from those mutated in STAT3 AD-HIES, as well as a residue located in the STAT3 N-terminal coiled:coil domain (Figure 2; not shown) [77–79].…”

“…A second individual developed T-cell large granular lymphocytic leukemia, indicating the malignant potential of de novo STAT3 GOF mutations [78]. Overall, a complex phenotype of autoimmunity and specific immune deficiencies presents with STAT3 GOF mutation [80]. While this disease has yet to be modeled in the murine system for pre-clinical studies, there is encouraging evidence that IL-6 inhibition or bone marrow transplantation may provide treatment options [79].…”

“…This phenotype may be due to impaired IL-10 signaling in DCs [218]. Moreover, as discussed above, early studies of humans with STAT3 GOF-mediated diseases have revealed surprising deficits in cells that exhibit STAT3-dependency in mice [78, 80]. Since many immune responses depend on interaction of multiple cell types, often mediated by cytokines, it is imperative to dissect primary and secondary responses in STAT3 LOF and GOF-associated disease.…”

Exome and genome sequencing for inborn errors of immunity

“…A similar phenomenon has been observed for STAT3 . LOF mutations in STAT3 cause AD hyper-IgE syndrome whereas GOF mutations, sometimes at the same position, lead to lymphoproliferation and auto-immunity (63–66). Mutations in DOCK8 typically result in AR combined immunodeficiency (CID), with severe eczema and elevated serum IgE levels, but they can also produce a CID phenotype without eczema or hyper-IgE (67, 68).…”

Verbascoside Inhibits Glioblastoma Cell Proliferation, Migration and Invasion While Promoting Apoptosis Through Upregulation of Protein Tyrosine Phosphatase SHP-1 and Inhibition of STAT3 Phosphorylation

“…Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), identified as a cytosolic phosphatase, is predominantly expressed in hematopoietic and epithelial cells, serving as a negative regulator of different signaling pathways, including signal transducer and activator of transcription 3 (STAT3) [12]. STAT3 is a member of the transcription factor family, which acts to change the expression of certain genes by transducing various cytokine signals [14]. Deregulation of STAT3 promotes proliferation and invasiveness of human glioblastoma cells [13].…”