Proteomimetics of Natural Regulators of JAK–STAT Pathway: Novel Therapeutic Perspectives

Abstract

The JAK-STAT pathway is a crucial cellular signaling cascade, including an intricate network of Protein–protein interactions (PPIs) responsible for its regulation. It mediates the activities of several cytokines, interferons, and growth factors and transduces extracellular signals into transcriptional programs to regulate cell growth and differentiation. It is essential for the development and function of both innate and adaptive immunities, and its aberrant deregulation was highlighted in neuroinflammatory diseases and in crucial mechanisms for tumor cell recognition and tumor-induced immune escape. For its involvement in a multitude of biological processes, it can be considered a valuable target for the development of drugs even if a specific focus on possible side effects associated with its inhibition is required. Herein, we review the possibilities to target JAK–STAT by focusing on its natural inhibitors as the suppressor of cytokine signaling (SOCS) proteins. This protein family is a crucial checkpoint inhibitor in immune homeostasis and a valuable target in immunotherapeutic approaches to cancer and immune deficiency disorders.

HSF1 is involved in immunotherapeutic response through regulating APOJ/STAT3-mediated PD-L1 expression in hepatocellular carcinoma

“…It is recently recognized that JAK-STAT signaling is closely associated with immune evasion and resistance to immune checkpoint inhibitors in HCC 30 , 31 as well as the function of STAT protein family depends on SH2 domain and play a crucial role in immune homeostasis. 32 Herein, we firstly observed the activation of JAK-STAT signaling in the condition of HSF1 expression alteration in HCC cells. The results showed that, after HSF1 overexpression, the ratios of p-STAT3(S727)/STAT3 and p-STAT3(Y705)/STAT3 were significantly increased while the ratios of p-STAT1/STAT1 and p-STAT5/STAT5 were not significantly changed in Huh7 cells ( Figure 3a-b ).…”

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

“…Aromatic face-to-face interactions occur in the second residue of all four JAKs, with phenylalanine (F 47 ) or tyrosine (Y 47 ) both being similar aromatic residues based on structural analysis. As the last residue of JAKs' hinge region, highly similar leucine (L 48 ) or valine (V 48 ), both act as HB donors. The linker region, which follows the hinge region, shows the same hydrophobic contact due to the similarity between the two bioisosteres cysteine 52 and serine 52 .…”

“…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. [48][49][50] As natural regulators of JAK-STAT pathway, SOCS proteins can effectively act as tumor suppressor and anti-inflammatory agents by creating a negative feedback loop against the pathway. 51,52 There are eight members of the SOCS protein family: SOCS1-7 and cytokineinducible SH2-containing protein (CIS).…”

JAK/STAT pathway: Extracellular signals, diseases, immunity, and therapeutic regimens

“…In addition, the JAK/STAT pathway receives regulation by multiple mechanisms, including that PIAS inhibits gene transcription by directly binding to STAT dimers and thereby blocking STAT binding to DNA. And SOCS protein can negatively regulate the JAK/STAT signaling cascade by inhibiting JAK activity, competing with STAT to bind phosphorylation sites on cytokine receptors, and inducing STAT proteasomal degradation (Boyle et al, 2009;La Manna et al, 2021) (Figure 1).…”