JAK-STAT Signaling in Autoimmunity and Cancer

Abstract

The JAK-STAT pathway is an essential cell survival signaling that regulates gene expressions related to inflammation, immunity and cancer. Cytokine receptors, signal transducer and activator of transcription (STAT) proteins, and Janus kinases (JAKs) are the critical component of this signaling cascade. When JAKs are stimulated by cytokines, STAT phosphorylation, dimerization, and nuclear translocation occur, which eventually impacts gene transcription. Dysregulation of JAK-STAT signaling is linked with various autoimmune diseases, including rheumatoid arthritis, psoriasis, and inflammatory bowel disease. This pathway is constitutively activated in human malignancies and leads to tumor cell survival, proliferation, and immune evasion. Oncogenic mutations in the JAK and STAT genes have been found in solid tumors, leukemia, and lymphoma. Targeting the JAK-STAT pathway is a viable and promising therapeutic strategy for the treatment of autoimmune diseases and cancers.

Keywords: JAK-STAT pathway; autoimmune diseases; cancer; inflammation.

Figure 1

Shows the four phases by which JAK/STAT controls nuclear communication and transmembrane receptors. (a) When cytokines attach to receptors, the receptor molecules dimerize, activating and phosphorylating both the intracellular tail of the receptors and JAKs. (b) These phosphorylated tyrosine sites create a docking site, which attracts the STAT protein. (c) The STATs can dimerize because they are phosphorylated and active. (d) The STAT-STAT Dimers move into the nucleus and control gene expression.

Figure 2

Domain architecture of essential proteins in the JAK-STAT signaling pathways. The figure illustrates the various domains represented in JAK (Janus Kinase), STAT (Signal Transducer and Activator of Transcription), SOCS (Suppressor of Cytokine Signaling), PIAS (Protein Inhibitors of Activated STATs), and SHP (SH2 domain-containing protein tyrosine phosphatase) proteins.

Figure 3

This figure illustrates the involvement of JAK-STAT signaling in autoimmunity and cancer. The pathway is activated by cytokines (IFNs, ILs, GM-CSF, etc.) and growth factors, leading to phosphorylation of JAKs and STATs. Different STATs (I–VI) then dimerize and translocate to the nucleus, where they regulate gene transcription, influencing the development of cancer and autoimmune diseases. The figure also lists specific diseases associated with the activation of each STAT, such as rheumatoid arthritis, leukemia, multiple sclerosis, and various cancers.

Figure 4

The figure illustrates the JAK/STAT signaling pathway and its role in cancer progression, highlighting its influence on tumor invasion, progression, autophagy, and apoptosis. This pathway promotes tumor invasion by regulating factors like ZEB1, JUNB, TWIST-1, and MMP, and supports EMT via IL-6 and SNAIL. The JAK/STAT pathway also inhibits autophagy and apoptosis, contributing to tumor survival and progression. Key factors like p16, p21, p53, and Bcl-xl are involved in these processes.