Signal Transducer and Activators of Transcription
Signal transducer and activators of transcription (STAT) protein are cytoplasmic transcription factor that have been known for cell tumor proliferation, survival, invasion, apoptosis and immune response. Each of these STAT family protein have a role and function when they are interacting with the cell in the human body. Among all of the STAT family protein the most important one is the STAT3. STAT3 is involved with many diseases as well as cancer. And the involvement it has with it is being associate with the other STAT family protein. This paper is to highlight on how STAT3 regulate signaling can cause a normal healthy cell into a cancerous cell.
In 1994, researchers have found out that STAT family proteins are latent cytoplasmic transcription factors are discovered as acute phase receptor factor [role of stat3 in cancer]. These STAT family proteins are located in the cytoplasm in a latent form and become active in response to stimulation by cytokines as well as growth factor hormones[loannis]. Within the STAT family proteins there are a total of seven member. Each member of the STAT family protein have a specific function and where they are located at. They are located on three different types of chromosomal cluster. One of them is on chromosome 2 which has STAT1 and STAT4. The second is the chromosome 17 which has STAT2 and STAT6. And finally chromosome 12 which has STAT3, STAT5a and STAT5b. Among all the STAT family protein the protein that have been studied on the most is the STAT3[loannis]. The reason being is that Janus kinases (JAKs), signal transducer and activator of transcription (STAT) protein are the target for cancer therapy. JAKs are cytoplasmic tyrosine kinases which in mammalians constitute a protein family [loannis]. There have been evidence shows that STAT3 is where the development, progression and maintenance of many human tumors [stat3 signaling in cancer]. There have been research finding that the STAT3 protein works with some of the other STAT family protein when it activates cancer and other diseases. Here are some background information of each STAT family protein and what are the main function that it does.
STAT3 is activated by phosphorylation of a single tyrosine residue at position 705 [role of STAT3]. This includes many tyrosine kinases that will catalyze this phosphorylation which include receptors with intrinsic tyrosine kinase activity as epidermal growth factor receptor (EGFR), vascular endothelial growth factor receptor, platelet derived growth factor receptor and colony stimulating factor-1. There are other residue that can phosphorylate STAT3 beside tyrosine is serine at position 727. Serine is able to phosphorylate STAT3 is required for STAT3 to be at a maximal transcriptional activity. Also STAT3 is also acetylated on a single lysine residue located at position 685 by histidine acetyl transferase. The acetylation here will regulate both transcriptional activity and homodimer stability. There are other factors that can activate STAT3 like for examples UV radiation, sunlight, stress, carcinogen, smoke, and infection [role of STAT3 in Cancer].But there are other researchers saying otherwise, even though there are increased levels of phosphorylated STAT3 have been detected in majority of human cancer and tumor-derived cell lines, there are no naturally occuring mutation that produce the activation on STAT3 that have been detected. [STAT3 signaling in cancer].
Figure 1 shows STAT3 signaling pathway, activation of the cell surface growth and cytokine receptors induces specific tyrosine phosphorylation (red small circle) of receptor to create a docking site for the recruitment of latent cytoplasmic STAT3 (dark gray geometries) that contain SH-2 domains (indentations) that recognize sites of tyrosine phosphorylation. Phosphorylation of STAT3 can be catalyzed by the intrinsic tyrosine kinase activity of the activated growth factor receptor (green elongated ovals). After recruitment of STAT3, it becomes activated by phosphorylation by JAK that coordinates with activated cytokine receptors (blue ovals). Then STAT3 will become a homodimer and translocated into the nucleus (red rings).
Figure 2 also shows the JAK-STAT3 pathway similar to figure 1. It has a diverse receptors with cytokine receptor as well as the G-protein coupled receptors, and Toll-like receptors (TLRs). The TLRs have an important role such as TLR9 and TLR4. They are an important activators for JAK-STAT3 pathway. Usually the receptor would bind to their cognate ligands but instead they will go under a conformational change and form interacting site for the adaptor proteins to spread signals. And the effect that it will cause the moment phosphorylated STAT3 is inside of the nucleus.
The moment that STAT3 is inside of the nucleus is can either attack on the epithelial cells or the immune cells. The epithelial cell that effect it will have on the cells to be survival or proliferated, migration and oncogenic transformation. On the immune cells, the cells would have a cell survival similar to the epithelial cells, pro- or anti-inflammatory cytokine production and pre-metastatic niche formation. But the most important one that will cause STAT3 to activate in diverse of tumors is interleukin-6 (revisting).
STAT3 in Cancer Cells with IL-6
The interleukin-6 (IL-6) is a traditional activator of STAT3 and it cause a conformational changes when there is a formation of a hexameric signaling. The result will have is that there is an activation on JAKs that is associated with a proline-rich, membrane-proximal cytoplasmic domain (revisting). IL-6 is a cytokine secreted by T-cells and macrophages. This is involved in immune and inflammatory responses. The IL-6 signaling launches with a ligand binding its receptor IL-6R and a common receptor subunit gp130 will create a hexameric receptor complex with two IL-6, IL-6R and gp130 [loansis].
There are two different types of signaling. One of them is called classical signaling of IL-6 where the signaling pathway is trigger in the early immune responses that will have consequently stimulating express with various proteins. Another signaling is called IL-6 trans-signaling where the IL-6 can bind to an existing soluble type of IL-6 receptor and form a complex that interacts with gp130. [loansis].
In figure 3 similar to the the previous figure but this shows the interaction with IL-6. It shows that when STAT3 becomes phosphorylated, it forms dimers and moves from the cytoplasm to the nucleus stimulating transcription of STAT3 target genes that includes cyclin D1, Bcl-xL, c-myc, Mc11 and vascular endothelial growth factor [loannis].