User:Immcarle59/sandbox

Lead (section copied from current JAK/STAT page)

**things in italics are parts I did not edit

The JAK-STAT signaling pathway transmits information from extracellular chemical signals to the nucleus resulting in DNA transcription and expression of genes involved in immunity, proliferation, differentiation, apoptosis and oncogenesis. The JAK-STAT signaling cascade consists of three main components: a cell surface receptor, a Janus kinase (JAK) and two Signal Transducer and Activator of Transcription (STAT) proteins.^[1] Disrupted or dysregulated JAK-STAT functionality can result in a variety of diseases including immune deficiency syndromes, inflammatory skin disorders, and cancers.^[1]

Mechanism

Flowchart describing the main steps involved in JAK/STAT signaling.

The binding of various ligands, usually cytokines, such as interferon, interleukin, and growth factors to cell surface receptors, activate associated JAKs, increasing their kinase activity.^[2] Activated JAKs then phosphorylate tyrosine residues on the receptor, creating binding sites for proteins possessing SH2 domains. SH2 domain containing STATs are recruited to the receptor where they are also tyrosine-phosphorylated by JAKs. These activated STATs form hetero- or homodimers and translocate to the cell nucleus where they induce transcription of target genes.^[3] STATs may also be tyrosine-phosphorylated directly by receptor tyrosine kinases, such as the epidermal growth factor receptor, as well as by non-receptor (cytoplasmic) tyrosine kinases such as c-src. The process of the JAK signal transduction is broken down into the following steps displayed in the flowchart below (10).

Currently, there are seven known STATs and four JAK proteins in mammals (8). Different cytokines work with different JAKs and STATs, giving rise to many different immune responses. Interleukin-2 (IL-2) receptor signaling is a great example of JAK/STAT signaling in T cells. These receptors have γ common chains, which are associated with JAK3, a specific kinase which then phosphorylates three tyrosines on the tail of the receptor. Phosphorylation then recruits Shc, an adapter protein. Sch then activates the mitogen-activate protein kinase (MAPK) pathway, which results in gene regulation by STAT5 (9). It is important to note that JAK3 is not expressed ubiquitously like other JAKs, the expression of JAK3 is highly regulated (8). This is only one example of a JAK signaling pathway; this pathway is also present in other mammalian cell signaling processes.

The pathway is negatively regulated on multiple levels. Protein tyrosine phosphatases remove phosphates from cytokine receptors and activated STATs.^[3] More recently identified suppressors of cytokine signaling (SOCS) inhibit STAT phosphorylation by binding and inhibiting JAKs or competing with STATs for phosphotyrosine binding sites on cytokine receptors.^[4] STATs are also negatively regulated by protein inhibitors of activated STAT (PIAS), which act in the nucleus through several mechanisms.^[5] For example, PIAS1 and PIAS3 inhibit transcriptional activation by STAT1 and STAT3, respectively by binding and blocking access to the DNA sequences they recognize.

Disease (new section)

Because Janus kinases are both type I and type II cytokine receptors and can signal everything from apoptosis to inflammation, they influence many immune disorders. Mutations in JAK functions can result in a serious autoimmune deficiency called severe combined autoimmune disorder (SCIDS) (9). Additionally, because they act as cytokine receptors, lack of JAK function can lead to inflammatory diseases (most notably skin diseases). (2)

Inflammatory skin disease

JAK signaling is also an important factor in some inflammatory skin diseases (ISD). When mutations occur in either the JAK or STAT proteins, the signaling chain will no longer function, and as a result cytokines can build up in the tissues causing excessive inflammation. For example, in psoriasis (a common ISD), dendritic cells produce IL-23 which then triggers the release of IL-17 and IL-22 from the innate lymphoid cells and the TH cells. These interleukins will not be able to properly signal, and will therefore build up in the tissue, causing the characteristic peeling and redness associated with psoriasis. (2)

SCIDs

Severe combined autoimmune disorder, or SCIDs, is defined as a complete lack of functioning T and B cells and other lymphocytes involved in adaptive immunity, making the individual susceptible to serious infections. One cause of SCIDs is a loss of function mutation in one of the genes that encodes JAK3 (9). Because this JAK has a γ common chain which it uses to receive signals from a variety of cytokines, including IL-2, IL-4, IL-7, IL-9, and IL-21, it is vital for this JAK to work in order for the cell to proliferate. (2) Without this signaling pathway, the individual will not develop functioning T cells, NK cells, or B cells. (10)

Cancer drugs and treatment

Studies have shown that certain cancer cells tend to express more JAK/STAT proteins than normal, indicating this signaling pathway as both cause of tumor cell proliferation and a target for chemotherapeutic drugs. JAK inhibitors have been proposed as novel drugs which could treat certain cancers such as leukemia, a cancer of the blood. JAKs are involved in erythropoietin (EPO) mediated hematopoiesis which is important in the maturation of red blood cells. EPO activates the JAKs that trigger hematopoietic stem cell differentiation and proliferation (11). Targeting and inhibiting these JAKs could regulate the maturation of bone marrow cells into red blood cells by eliminating the effects of EPO signaling (3)(7). Blocking these JAKs could be beneficial in leukemia treatment because it regulates cell growth and proliferation.

Bibliography:

1. Inflammatory skin diseases: https://www.ncbi.nlm.nih.gov/pubmed/28555727
2. New JAK inhibitor drugs: https://www.sciencedirect.com/science/article/pii/S1359644603030149?via%3Dihub
3. JAK inhibitors: http://www.tandfonline.com/doi/abs/10.1517/13543784.2013.774373?journalCode=ieid20
4. Hematopoiesis and JAK/STAT signaling: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2006.06206.x/epdf
5. Basic SCIDs information: https://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/severe-combined-immune-deficiency-and-combined-immune-deficiency
6. Kuby Immunology textbook.
7. Erythropoietin mediated bone formation is regulated by mTOR signaling: https://www.ncbi.nlm.nih.gov/pubmed/21898543
8. The Janus kinases: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC545791/
9. Interleukin-2 Receptor Signaling: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2946796/

Notes on JAK-STAT signaling pathway page:

• Citations are included for everything already

• This page is off to a good start but needs more information.
• Very little detail in the article in general- the introduction is unclear about the practical or physical outcome of this signalling pathway.
• There's no section on what happens when things go wrong with this pathway- are there diseases that affect this pathway?
• In general, more specificity is needed throughout the whole article, though the mechanism section needs it most of all. The one diagram given isn't super informative- perhaps it would be helpful to create another diagram? Or, display the crystal structure of some of the proteins involved in this signalling pathway?
• Cancer therapy is mentioned: I want to do more research on this.

https://apps.webofknowledge.com/full_record.do?product=WOS&search_mode=GeneralSearch&qid=5&SID=5DyTYqemclu137cRFwj&page=1&doc=4&cacheurlFromRightClick=no (go back and figure out what this link is for).

Plans for improvement:

I plan on adding a section about how this signalling pathway is important in cancer and other diseases. Hopefully, this will make the page more accessible and help people understand this pathway's affect on diseases and drug development. I also plan on editing it more generally and trying to get it to flow better. I may also add a little more information to the leading paragraph.

Working Bibliography:

1. JAK/STAT and interferons: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5732261/
2. Inflammatory skin diseases: https://www.ncbi.nlm.nih.gov/pubmed/28555727
3. New JAK inhibitor drugs: https://www.sciencedirect.com/science/article/pii/S1359644603030149?via%3Dihub
4. Gastric Carcinoma: https://www.spandidos-publications.com/ijo/47/5/1617
5. STAT inhibitor patient review: http://www.tandfonline.com/doi/abs/10.1517/13543776.2015.1086749?journalCode=ietp20
6. Autoimune diseases: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4181323/
7. JAK inhibitors: http://www.tandfonline.com/doi/abs/10.1517/13543784.2013.774373?journalCode=ieid20
8. Hematopoiesis and JAK/STAT signalling: http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2141.2006.06206.x/epdf
9. Basic SCIDs information: https://primaryimmune.org/about-primary-immunodeficiencies/specific-disease-types/severe-combined-immune-deficiency-and-combined-immune-deficiency
10. Kuby Immunology textbook!