Signal transducer and activator of transcription 6 (STAT6) (STAT6)

Signal transducer and activator of transcription 6 (STAT6) is a critical mediator of Type 2 immune responses, functioning downstream of the IL-4 and IL-13 receptors (UniProt P42226). Upon cytokine stimulation, STAT6 is phosphorylated by Janus kinases (JAKs), which triggers its dimerization via the Src Homology 2 (SH2) domain. These dimers translocate to the nucleus to initiate the transcription of genes involved in Th2 cell differentiation, B-cell isotype switching to IgE, and recruitment of eosinophils (PubMed: 33431135). The SH2 domain is the most druggable pocket of the protein, as it is required for both recruitment to the receptor complex and subsequent dimerization. Dysregulation of STAT6 is central to the pathogenesis of asthma, atopic dermatitis, and chronic rhinosinusitis, and it is also implicated in the survival of certain B-cell malignancies like Hodgkin lymphoma. Current therapeutic development focuses on small-molecule inhibitors and PROTAC degraders, such as KT-621, that target the SH2 domain to achieve high selectivity over other STAT family members (Kymera Therapeutics).

Other names

IL-4-induced transcription factorSTAT-6D12S1644STAT6BSTAT6C

Inhibition of SH2 domain-mediated dimerization and DNA binding; Targeted protein degradation via PROTACs