STAT6

Fig1. The post-translational modification of STAT6. (Hao Huang, 2020)

What is STAT6 protein?

STAT6 gene (signal transducer and activator of transcription 6) is a protein coding gene which situated on the long arm of chromosome 12 at locus 12q13. The protein encoded by this gene is a member of the STAT family of transcription factors. In response to cytokines and growth factors, STAT family members are phosphorylated by the receptor associated kinases, and then form homo- or heterodimers that translocate to the cell nucleus where they act as transcription activators. This protein plays a central role in exerting IL4 mediated biological responses. It is found to induce the expression of BCL2L1/BCL-X(L), which is responsible for the anti-apoptotic activity of IL4. The STAT6 protein is consisted of 847 amino acids and STAT6 molecular weight is approximately 94.1 kDa.

What is the function of STAT6 protein?

STAT6 is a protein that plays a pivotal role in regulating immune responses, particularly in the development of allergic conditions and the differentiation of T helper 2 (Th2) cells. When activated, STAT6 dimerizes and translocates to the nucleus, where it acts as a transcription factor to regulate the expression of genes involved in immune responses, cell growth, and differentiation. It is activated by various cytokines, including interleukin-4 (IL-4) and IL-13, which are crucial for Th2 cell-mediated immune responses. The activation of STAT6 is a critical step in the signaling pathways that lead to the production of Th2-associated cytokines and the manifestation of allergic reactions.

STAT6 Related Signaling Pathway

The JAK/STAT pathway is tightly regulated by negative feedback mechanisms, including the activation of suppressors of cytokine signaling (SOCS) proteins and protein tyrosine phosphatases (PTPs), which can dephosphorylate and inactivate STAT6. The binding of these cytokines leads to receptor dimerization, which brings the associated Janus kinases (JAKs) into proximity, activating them. Activated JAKs phosphorylate STAT6 on a specific tyrosine residue. This phosphorylation is essential for STAT6 activation. Once phosphorylated, STAT6 monomers dimerize through reciprocal phosphotyrosine-SH2 domain interactions and translocate to the nucleus.

STAT6 Related Diseases

Its dysregulation has been implicated in a spectrum of diseases, predominantly in the realm of allergic conditions and malignancies. Allergic diseases such as asthma, atopic dermatitis, eosinophilic esophagitis, and food allergies are often Th2-mediated, and STAT6 plays a crucial role in their pathophysiology by promoting Th2 differentiation and IgE production. Furthermore, STAT6's influence extends to the development and progression of certain types of cancer, including lymphomas and solitary fibrous tumors, where it contributes to tumor growth and the modulation of the tumor microenvironment. In pulmonary diseases, STAT6 is a key player in asthma pathogenesis and is also involved in acute respiratory distress syndrome (ARDS), pulmonary fibrosis, and the pulmonary antiviral response.

Bioapplications of STAT6

STAT6, with its pivotal role in immune responses and cell signaling, offers a rich landscape for bioapplications, particularly in the fields of immunology and oncology. In immunology, STAT6's ability to regulate Th2 cell differentiation and IgE production positions it as a potential target for therapeutic intervention in allergic diseases. Additionally, its involvement in the immune response to helminthic parasites suggests applications in combating parasitic infections. In oncology, the connection between STAT6 and tumor development, especially in lymphomas and fibrous tumors, makes it a candidate for targeted cancer therapies. Moreover, STAT6's role in the polarization of tumor-associated macrophages highlights its potential in modulating the immunosuppressive tumor milieu.