Section 3.2.5: JAK-STAT signaling pathway (from DOI: 10.1038/s41392-020-0110-5)
From publication: "Targeting cancer stem cell pathways for cancer therapy" published as Signal Transduct Target Ther; 2020 ; 5 8: DOI: https://doi.org/10.1038/s41392-020-0110-5
Section 3.2.5: JAK-STAT signaling pathway
The Janus kinase/signal transducers and activators of transcription (JAK-STAT) signaling pathway is a signal transduction pathway that is stimulated by cytokines. This pathway is involved in many important biological processes, such as cell proliferation, differentiation, apoptosis, and immune regulation. Compared with the complexity of other signaling pathways, this signaling pathway is relatively simple. There are three components: the tyrosine kinase-related receptor, the tyrosine kinase JAK, and the transcription factor STAT. Many cytokines and growth factors transmit signals through the JAK-STAT signaling pathway, including interleukin-2-7, granulocyte/macrophage colony-stimulating factor, growth hormone, EGF, PDGF, and interferon. These cytokines and growth factors have corresponding receptors on the cell membrane. The common characteristic of these receptors is that the receptor itself does not have kinase activity, but there is a binding site for the tyrosine kinase JAK in the cells. After binding with ligands, tyrosine residues of various target proteins are phosphorylated through JAK activation to achieve signal transduction from the extracellular to intracellular space. The JAK protein family consists of four members: JAK1, JAK2, JAK3, and Tyk2. JAK proteins have seven JAK homology (JH) domains in their structures. The JH1 domain is the kinase domain, the JH2 domain is the "pseudo" kinase domain, and JH6 and JH7 are the receptor binding domains. STAT is called "signal transducer and activator of transcription". As the name implies, STAT plays a key role in signal transduction and transcriptional activation. At present, seven members of the STAT family (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6) have been identified. The structure of STAT protein can be divided into the following functional regions: N-terminal conserved sequence, DNA-binding region, SH3 domain, SH2 domain, and C-terminal transcriptional activation region. Generally, many cytokines and growth factors integrate with tyrosine kinase-related receptors. After receiving the signal from the upstream receptor molecule, JAK is quickly recruited to and activates the receptor, resulting in JAK activation to catalyze tyrosine phosphorylation of the receptor. The phosphorylated tyrosine on the receptor molecule, which is a signaling molecule, can bind with the SH2 site of STAT. When STAT binds to the receptor, tyrosine phosphorylation of STAT also occurs, which forms a dimer and enters the nucleus. As an active transcription factor, the STAT dimer directly affects the expression of related genes and then changes the proliferation or differentiation of target cells.
Constitutive activation of JAKs and STATs was first recognized as being associated with malignancy in the 1990s. Based on current studies, JAK2 mutation and abnormal activation of STAT3 are prone to occur in many tumors. Mutations in JAK2 have been reported in the majority of patients with myeloproliferative neoplasms, such as polycythemia vera, myelofibrosis, and thrombocythemia. These disorders are caused by the overexpansion of hematopoietic precursors, which are often clonal and can result in leukemia. Several lines of evidence show that constitutive activation of JAK2 and STAT3 in the absence of any stimulating ligand occurs in polycythemia vera. Moreover, studies have also found aberrant activation of STATs in human cancers, such as head and neck cancer, endometrial cancer, breast cancer, diffuse large B cell lymphoma, HCC, colorectal cancer, glioma, and colon cancer. Furthermore, aberrant STAT5 signaling has been found in the pathogenesis of hematologic and solid organ malignancies.
The JAK/STAT pathway is evolutionarily conserved. This pathway promotes the survival, self-renewal, hematopoiesis, and neurogenesis of ESCs. This pathway is also activated in CSCs. The persistent activation of STAT3 significantly promotes cell survival and the maintenance of stemness in breast CSCs. IL-10 induces cell self-renewal, migration, and invasion in non-small-cell lung CSCs. IL-6 activates the JAK1/STAT3 pathway in ALDHhigh CD126+ endometrial CSCs. Furthermore, IL-6 also induces the conversion of nonstem cancer cells into cancer stem-like cells in breast cancer by the activating downstream Oct4 gene. Oct4 also activates the JAK1/STAT6 pathway in ovarian CSCs. In CD44+CD24- breast and colorectal CSCs, erythropoietin, and IL-6 activate the JAK2/STAT3 pathway. Retinol-binding protein 4 activates JAK2/STAT3 signaling by its STRA6 receptor in colon CSCs. HIF-1alpha enhances the self-renewal of glioma stem-like cells by the JAK1/STAT3 pathway. AJUBA is a scaffold protein that participates in the regulation of cell adhesion, differentiation, proliferation, and migration and promotes the survival and proliferation of colorectal CSCs via the JAK1/STAT1 pathway.
Moreover, microRNAs are also involved in activating JAK/STAT signaling by inhibiting negative regulatory factors of JAK2/STAT3. For example, miR-500a-3p targets multiple negative regulators of the JAK2/STAT3 signaling pathway, such as SOCS2, SOCS4, and PTPN, in HCC stem cells, leading to constitutive activation of STAT3 signaling. MiR-30 targets SOCS3 in glioma stem cells. Mir-93 downregulates the expression of JAK1 and STAT3 to induce the differentiation of breast CSCs. Mir-218 negatively regulates the IL-6 receptor and JAK3 gene expression in lung CSCs. In addition, some endogenous or exogenous genes inhibit JAK/STAT signaling in CSCs. Von Hippel-Lindau suppresses the tumorigenicity and self-renewal ability of glioma stem cells by inhibiting JAK2/STAT3. Although there are few studies on JAK in CSCs, there is a role for JAK/STAT signaling in the survival, self-renewal, and metastasis of CSCs.
