Alex Dean

JAK-STAT Signaling Pathway and Leukemia

Blog Post created by Alex Dean on Dec 28, 2018

JAK-STAT signaling pathway

The JAK-STAT signaling pathway is a signal transduction pathway stimulated by cytokines discovered in recent years, which is involved in many important biological processes such as cell proliferation, differentiation, apoptosis and immune regulation. Compared with other signaling pathways, this signaling pathway is relatively simple to transfer. It consists of three components, namely tyrosine kinase-related receptor, tyrosine kinase JAK and transcription factor STAT.

As mentioned above, the transfer of the JAK-STAT signaling pathway is relatively simple compared to other signaling pathways. The signaling process is as follows: Binding of cytokines to the corresponding receptor causes dimerization of the receptor molecule, which allows the JAK kinases coupled to the receptor to be close to each other and activated by interactive tyrosine phosphorylation. After JAK activation, the tyrosine residues on the catalytic receptor are phosphorylated, and then these phosphorylated tyrosine sites form a "docking site" with the surrounding amino acid sequence, and STAT protein that contains the SH2 domain was recruited to this "parking site." Finally, the kinase JAK catalyzes the phosphorylation of the STAT protein bound to the receptor, and the activated STAT protein enters the nucleus as a dimer to bind to the target gene and regulate gene transcription. It is worth mentioning that a JAK kinase can be involved in the signal transduction of many cytokines. A cytokine signaling pathway can also activate multiple JAK kinases, but cytokines have certain choices for activated STAT molecules. For example, IL-4 activates STAT6, while IL-12 specifically activates STAT4.

JAK-STAT signaling pathway and leukemia

The JAK-STAT signaling pathway is widely used, and many studies have focused on immune response and immune regulation. Combined with the latest issue of Cancer Cell, the relationship between STAT5 signaling and leukemia JMML, we will focus on the pathogenesis of JAK-STAT signaling pathway and leukemia.

Leukemia is a malignant disease of hematopoietic tissue, also known as "blood cancer". It is one of the most common malignant tumors in China. The disease ranks first among the malignant diseases of young people. Leukemia cells exhibit diametrically opposite biological properties compared to normal hematopoietic cells. Normal hematopoietic cells continue to differentiate and mature under the action of cytokines, while leukemia cells show that the differentiation process is blocked and then proliferate without restriction. This suggests that abnormalities in intracellular signaling pathway play an important role in the formation of leukemia. Many studies have shown that abnormal activation of the JAK-STAT signaling pathway plays an important role in the pathogenesis of leukemia.

The continuous activation of JAK-STAT signaling pathway is prevalent in leukemia cells. Therefore, STAT protein has become one of the key indicators for detection. Overexpression of STAT molecules is often found in many malignant proliferative diseases, and the STAT family is the most activated in tumors of the hematopoietic system, including leukemias and lymphomas. For example, STAT1, STAT3, and STAT5 are the most common persistent activation in leukemia. Signal protein. Different types of leukemia cells can be expressed as abnormal activation of one or more STAT proteins. For example, in lymphocytic leukemia and monocytic leukemia, the common activation of STAT5 is common; while the myeloid leukemia cells are continuously activated by STAT3.

Kinase JAK plays a key role in the activation of the entire signaling pathway. To date, we have found many point mutations in the JAK gene in human leukemia cells, some of which cause the kinase JAK to continuously activate the STAT protein. The most typical example is the aberrant activation of the JAK-STAT signaling pathway by the JAK2 V617F mutation (proline mutation of the 617th proline of the protein JAK2 to phenylalanine). A statistical analysis of leukemia patients showed that 4 of 222 patients with AML (acute myeloid leukemia) developed JAK2 V617F mutations, 3 of which had a history of MPD (myeloproliferative disorders). In addition, JAK2 V617F mutation occurred in 9 of 116 patients with CML (chronic myeloid leukemia). In addition, other mutant forms of JAK protein are also closely related to many leukemia types.

Although there is ample evidence that the sustained activation of the JAK-STAT signaling pathway is closely related to leukemia, the occurrence of leukemia is the result of multiple genetic abnormalities, and the pathogenesis involves multiple steps. Therefore, further research is needed to explore the detailed mechanisms in the formation of JAK-STAT signaling and leukemia. In addition, since the occurrence of leukemia is closely related to the activation of JAK-STAT, proteins such as JAK and STAT are likely to be the best drug targets for the treatment of leukemia. Designing specific inhibitors for these proteins will undoubtedly bring new treatment to leukemia.

Author's Bio:

BOC Sciences is one of the fastest growing chemical companies whose quality products (such as inhibitors, APIs, metabolites, impurities) and services (such as biosynthesis, carbohydrate synthesis) are widely recognized across the nation. To offer the public some scientific insights concerning cancer, scientists at this company have compiled a series of articles regarding various pathways, including Hedgehog Signaling Pathway, PI3K/Akt Signaling Pathway, Gamma Secretase Signalling Pathway, HIF Signaling Pathway, p38 Signaling Pathway, CTLA4 Signaling Pathway, NOD-like Receptor Signaling Pathway, NF-κB Signaling Pathway, and more.