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Browse All Figures Return to Figure. GM-CSF receptors have been identified on most types of myeloid progenitors, mature monocytes, neutrophils, eosinophils, basophils, and dendritic cells and mainly contribute to defense mechanisms against bacterial infections Leptin is a cytokine normally secreted from adipose tissue, and is involved in regulating energy consumption and appetite Interaction of leptin with the leptin receptor which is categorized as a type I cytokine receptor initiates the signaling cascade by phosphorylating associated JAK2. This receptor, activated by chemokine stromal cell-derived factor SDF-1alpha , becomes tyrosine phosphorylated through activation and association with the receptor of JAK2 and JAK3 kinases, which in turn recruit and tyrosine phosphorylate multiple STAT family members In a manuscript, Mellado et al.
On the other hand, CXCR4 has been found to be a prognostic marker in a variety of cancers, including breast cancer In , Ali et al. However, the exact mechanism was not clear. In , Andl et al. Other reports since then have confirmed this link, and indicated the regulation of PD-L1 expression, among other intracellular roles, via this link — There are a few reports that claim toll-like receptors TLRs could also activate STAT3, which is one of the pathways for this family of receptors to play a role in tumor development ; however, their involvement is contentious.
It has been reported that TLR4 overexpression could lead to STAT3 activation in intestinal epithelial cells, which also correlates with the clinical outcomes of colon adenocarcinoma Upregulation of IL-6 by TLR4 is also reported in lymphoma , as a possible mechanism in the carcinogenesis.
TLR9 is overexpressed in glioma stem cells, and a correlation between the expression level of TLR9 and survival rate in glioblastoma has been reported In , Pezet et al. Unlike RTKs, cytokine receptors do not possess intrinsic kinase domain, and therefore, rely on JAK family to transfer the signal to the cytoplasmic components of the cascade JAK is associated with cytoplasmic domains of cytokine receptors via JAK binding sites that are located close to the membrane and forms a complex that is equivalent in function to RTKs However, the where and when of this association has been a topic of discussion JH1 and JH2 form the kinase and pseudokinase domains, respectively It is evident that different receptors have specific preferences for the JAK family protein they use as signaling effector, which means there is an obligate relationship between the receptor and the specific JAK protein s activated However, in many cases, it has been shown that in the absence of the specific JAK family member, other proteins in the family have taken the responsibility and transferred the signal.
The next step in this signaling cascade is the recruitment of members of STAT family of proteins. As their name indicates, STATs act both as signal transducer and transcription factor; however, two structural components make them unique among transcription factors: an SH2 domain and a highly conserved C-terminal tyrosine residue It is this tyrosine residue that is phosphorylated by activated JAKs. A similar specificity observed with JAKs is seen here as well, where specific members of STAT family respond to a defined set of stimuli and receptors.
After activation by tyrosine phosphorylation, STATs become dimerized and translocate into the nucleus, where they act as transcription factors. STAT1 has been reported to exist as pre-formed homodimers, and phosphorylation induces reorientation anti-parallel to parallel conformation , which presumably could be true for other STATs as well While translocation between cytoplasm and nucleus is a regular occurrence, the nuclear envelope provides a barrier that prevents free diffusion of large molecules more than 40—60 kilo Dalton in molecular weight.
These large molecules, including STATs usually require a specific transport receptor for facilitated transport The translocation of STATs into nucleus via importins is a subject of discussion. STAT3, 5, and 6 could be translocated into nucleus in the un-phosphorylated form as well STATs have demonstrated the capability to activate the transcription of non-active genes in a few minutes STAT family of proteins play multiple roles in cancer cells, and specifically, STAT3 has been shown to enhance cancer cell proliferation, migration, and survival, in addition to suppression of antitumor immune response This ability of STATs to integrate the signal from a wide variety of signaling cascades indicates the possibility of regulation of a variety of genes through this family of transcription factors that serve different mechanisms involved in growth, differentiation, and survival.
STAT1 homodimers are also formed. Both dimers seem to promote the expression of genes that enhance growth arrest and apoptosis Table 3. For instance, STAT1 is involved in expression of several caspases, as executives of apoptosis Based on the downregulation and activation pattern of downstream proteins, STAT1 seems to be involved in controlling the cell growth, enhancing vascularization, and inducing cell death, which are all characteristics that inhibit tumor growth.
Table 3. Selected survival-related genes regulated by members of STAT family of proteins. There is little information available about the formation of STAT2 homodimers, and the role of STAT2 as an independent transcription factor is largely unknown and controversial STAT2 activation has been linked to increased expression level of Cluster of differentiation CD 40 and CD80 , receptors involved in a multiple-step T-cell activation model It also seems to play a crucial role in development, as knocking down STAT3 in mice has been proven to be lethal to the embryo It has been reported that non-phosphorylated STAT3 present in nucleus could also affect the expression of many oncogenic proteins, independently, or after forming complexes with other transcription factors, e.
Among well-known proteins that are overexpressed by STAT3 activation, Mcl-1, Bcl-2, Bcl-XL, and survivin are anti-apoptotic proteins that play a crucial role in cancer cell survival , , , cyclin D1 and c-Myc enhance proliferation , and VEGF promotes angiogenesis, which is required for tumor growth On the other hand, STAT5 is the other member of the family usually associated with cancer. STAT5 is involved in expression of many proteins that are linked to STAT3 as well, and therefore seems to contribute to similar outcomes cell survival and enhanced proliferation.
Id-1 is a protein involved in cancer progression, angiogenesis, and cell survival STAT6 activation seems to be triggered mainly by IL-4 and IL, and the loss of these cascades has been reported to impaired T-helper 2 cell differentiation and development of certain types of leukemias and lymphomas , respectively.
Majoros et al. MicroRNAs miRNAs are part of cellular gene expression regulators that can significantly change the phenotypic characteristics of the cell. They are expressed as hairpin structures, transformed in a multi-step process to a single strand RNA, and are incorporated into the RNA-induced silencing complex RISC to identify and bind to a partial or perfect complementary match on targeted mRNAs It has been hypothesized that blocking this signaling pathway could inhibit cancer progression as a single therapy, or in combination with other anticancer agents.
The small molecule drugs targeting these proteins in clinical trials or used in clinics are summarized in Table 4. A quick look at the table reveals a few facts:. The other explanation could be based on the hypothesis that upstream proteins might be involved in cross-talk with other signaling cascades, and therefore, by targeting JAKs we could also interfere with other mechanism involved in cancer progression.
The emphasis on JAKs is also apparent in number of drugs in clinics and clinical trials compared to drugs targeting STATs which are mostly still in pre-clinical stages ;. This is mostly due to the fact that STAT3 has been one of most promising targets for molecularly targeted treatment. In fact, cancer seems to be the dominant target for these therapeutic approaches. Autoimmune diseases e. Table 4.
JAK-STAT signaling pathway - Wikipedia
Fedratinib reached Phase III clinical trials; however, a report published in indicates that the clinical development has been discontinued due to toxic effects in some patients most importantly encephalopathy , despite significant reduction of splenomegaly and symptom of myelofibrosis Another interrupted development was recently reported for Pacritinib a specific JAK2 inhibitor in Phase III clinical trial, due to patient deaths, despite previous reports on its efficacy and safety in myelofibrosis Recent reports also indicate development of TYK2-specific inhibitors, including NDI which has shown promising results in acute lymphoblastic leukemia A comprehensive review on investigational JAK inhibitors was recently published by Musumeci et al.
Due to a wider range of targets for these approaches, a larger number of effectors have been silenced via RNAi-based attempts, which include the downstream proteins activated by this pathway, and have been reviewed previously Antisense oligonucleotides ASOs have also been studied for silencing proteins involved in this pathway.
Recently, Hong et al. Sen et al.
Quick et al. Crosstalk between JAK and other well-known signaling pathways has been documented in recent years. In , Levine et al. Figure 2 illustrates the central role of JAK protein in activation of these three major pathways. Despite promising tumor suppression in animal studies as a result of inhibition of this pathway, however, the safety issues have marred the success of this therapeutic approach in clinical settings to some extent.
Also, due to the versatile nature of the pathway, and potential crosstalks with multiple alternative pathways, a monotherapy-based approach might not create reliable results on the long term. A more systematic exploration of intra- and inter-pathway connections would be helpful in understanding the molecular mechanisms of the signal transduction in this cascade, as well, as identification of novel targets in cancer therapy. Both authors made an intellectual contribution to this work. Literature search, tables and figures are mostly done by EB.
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How cells signal to each other
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Intracellular Signal Transduction: The JAK-STAT Pathway
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