Fig. 1.

Mechanisms for disruption of STAT3-related signaling in STAT3-HIES and its phenocopies. 1. ZNF341 positively regulates STAT3 transcription [27]. 2. IL-6 and IL-11 bind to their respective receptors and form a complex with GP130, then sequentially phosphorylate first a JAK, then STAT3. IL-6 signaling may be disrupted by mutations in IL6R, while IL-11 signaling may be disrupted by IL11R mutations, and both may be affected by mutated IL6ST or STAT3. 3. Mutations in the SH2 domain of STAT3 impact tyrosine phosphorylation, while mutations in the DBD domain impact on STAT3 dimers binding to DNA [108]. 4. STAT3 activates ERBIN and disrupts TGFβ-SMAD2/3 signaling by sequestering phospho-SMAD2/3 in the cytoplasm and preventing transcriptional action of TGFβ [84]. This may be disrupted by mutations in STAT3 or ERBB2IP. Key: STAT3, signal transducer and activator of transcription 3; ERBIN, ERBB2-interacting protein; ZNF341, zinc finger protein 341; GP130, glycoprotein 130