Evolving cognition of the JAK-STAT signaling pathway: autoimmune disorders and cancer

Abstract

The Janus kinase (JAK) signal transducer and activator of transcription (JAK-STAT) pathway is an evolutionarily conserved mechanism of transmembrane signal transduction that enables cells to communicate with the exterior environment. Various cytokines, interferons, growth factors, and other specific molecules activate JAK-STAT signaling to drive a series of physiological and pathological processes, including proliferation, metabolism, immune response, inflammation, and malignancy. Dysregulated JAK-STAT signaling and related genetic mutations are strongly associated with immune activation and cancer progression. Insights into the structures and functions of the JAK-STAT pathway have led to the development and approval of diverse drugs for the clinical treatment of diseases. Currently, drugs have been developed to mainly target the JAK-STAT pathway and are commonly divided into three subtypes: cytokine or receptor antibodies, JAK inhibitors, and STAT inhibitors. And novel agents also continue to be developed and tested in preclinical and clinical studies. The effectiveness and safety of each kind of drug also warrant further scientific trials before put into being clinical applications. Here, we review the current understanding of the fundamental composition and function of the JAK-STAT signaling pathway. We also discuss advancements in the understanding of JAK-STAT–related pathogenic mechanisms; targeted JAK-STAT therapies for various diseases, especially immune disorders, and cancers; newly developed JAK inhibitors; and current challenges and directions in the field.

Network pharmacological analysis on the mechanism of Coix seed decoction for osteoarthritis of the knee

“…[54] On the other hand, the overexpression of inflammatory factors can also activate corresponding pathways in the human body to inhibit inflammatory responses. For example, [60–62] IL-6 can activate JAK-STAT signaling pathway, which is one of the few multi-effect cascades. IL-6 first binds to the receptor on the cell membrane to activate the receptor, and the activated receptor induces JAK phosphorylation to further phosphorylate STAT-3, and the activated STAT-3 dimerizes into the nucleus to regulate the expression of anti-apoptotic genes such as Bcl-2, MCL1, and cell cycle-related genes such as c-Myc and p21.…”

Insight into Janus kinases specificity: From molecular architecture to cancer therapeutics

“…234 In addition, HB interaction with R901 1 was not recorded in TYK2 which means the lack of TYK2 (JH1 domain) selective inhibitor study. Besides, the large hydrophobic pocket composed of G904 4 , E905 5 and G906 6 in TYK2 makes it easy to form hydrophobic interactions with all three residues compared to other three JAK members. This strategy could be utilized to lightly improve TYK2 selectivity.…”

“…26,27 The activation catalyzes phosphorylation of receptor tyrosine residues, of JAKs themselves and of signal transducers and activators of transcriptions proteins. 5 Finally, these phosphorylated STAT (P-STAT) dimerize and translocate to the nucleus where they bind to specific DNA binding sites 28 to regulate genes transcription and cellular function involved in hematopoiesis, [29][30][31] proliferation, 5,[32][33][34] apoptosis, [35][36][37] differentiation, 38,39 metabolism, 40,41 immune modulation, [42][43][44] and malignancy 5,45 and the detailed information regarding the corresponding biological functions is summarized in Figure 1C. 42,46,47 Suppressor of cytokine signaling (SOCS) proteins play a critical role in regulating immune response disorders related to cancer based on the JAK-STAT pathway.…”

“…51,52 There are eight members of the SOCS protein family: SOCS1-7 and cytokineinducible SH2-containing protein (CIS). 5,53,54 Among these members, SOCS1 and SOCS3 have been extensively studied because they both have a kinase inhibitory region (KIR) in the N-terminal section, which allow then to inhibit the downstream signaling pathway. 12,[55][56][57] Researchers have designed and tested proteomimetics of SOCS1 and SOCS3 based on the presence of KIR.…”

“…44,55,60 As shown in Figure 1E, the JAK structure is composed of seven JAK homology modules: JH7-JH1 (from N-terminus to the C-terminus), which were further divided into four domains-FERM (F for 4.1 protein, E for ezrin, R for radixin and M for moesin) domain, SH2 domain (Src Homology 2 domain), pseudokinase domain and Kinase domain-based on their biochemical functions. 5,61 The kinase domain (JH1) and pseudokinase domain (JH2) have been extensively studied as attractive JAK targets in the field of drug discovery. 62 The detailed structural analysis will be discussed in Section 2.…”