JAK-STAT PATHWAY IN DEVELOPMENT AND HOMEOSTATIC PROCESSES

The JAK-STAT pathway, also called Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT) signaling pathway, is a universally expressed intracellular signal transduction pathway. It plays a central role in many crucial biological processes, including immune responses, cell proliferation, differentiation, angiogenesis, apoptosis, survival...depending on the physiological signal.
This pathway play a pivotal role in the transfer of signals from cell membrane receptors to the nucleus ^(1,3).

KNOWN COMPONENTS OF JAK-STAT PATHWAY

The basic components of this pathyway are JAKs and STATs. In addition to ligands (cytokines or growth factors), cytokine receptors I and II, and suppressors of cytokine signaling (SOCSs).

Janus Kinase family, a non-transmembrane tyrosine kinase proteins. It contains four different molecules (JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2)).
Seven STAT family members (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6).

Ligands, such as cytokines, growth hormone and factor, as well as their respective receptors, activates the JAK/STAT pathway. The activated JAKs phosphorylate the cytoplasmic tyrosine residues of the receptor. This creates binding sites for other signaling molecules that contain a Src homology 2 (SH2) domain, such as STATs. Then JAKs phosphorylate STATs.

Several molecules can negativly regulates jak stat pathway. Among them SOCS, protein inhibitor of activated STAT (PIAS) and protein tyrosine phosphatases (PTPs) ^(2,3).

The schematic structures of the JAK and STAT proteins and overview of the JAK/STAT pathway.

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Membrane cytokine receptors have cytoplasmic tails in which inactive JAKs associate constitutively. The interaction of cytokines or growth factors with their receptors (type I and II) induces dimerization/oligomerization of these receptors. It should be mentioned that some cytokine receptors, such as GHR and EpoR, show pre-formed dimers. In both cases, the interaction between the cytokine and its receptor induces a conformational change in the cytoplasmic domain. This interaction results in the juxtaposition of JAKs, leading to their autophosphorylation or transphosphorylation by other JAKs or other families of tyrosine kinases. The activated JAKs then phosphorylate the receptor’s cytoplasmic tails on tyrosine residues, creating sites that allow the binding of other signaling molecules that contain an SH2 domain (such as STAT proteins). Cytoplasmic STATs then bind to phosphorylated receptors, becoming substrates for JAKs, which phosphorylate STATs on highly conserved tyrosine residues. After their phosphorylation, STATs form homodimers or heterodimers that are capable of translocating to the nucleus and activating gene transcription. The JAK/STAT pathway is negatively regulated by the suppressors of cytokine signaling (SOCS), as well as by the protein inhibitor of activated STAT (PIAS) and protein tyrosine phosphatases (PTPs) ⁽⁴⁾ .

JAK-STAT PATHWAY AND DISEASES

Among the STAT molecules, STAT3 and STAT5 were frequently found to be persistently activated in a variety of cultured human cancer cells and primary cells derived from cancer patients. They participate in the appearance, development and survival of cancer cells.

Besides its important impact in cellular signaling, the JAK/STAT pathway enters into several diseases. Among this Rheumatoid arthritis, Parkinson’s disease, multiple sclerosis, sepsis, inflammatory bowel disease, COVID-19 infection... ^(1,2,4,5).

Aberrant JAK/STAT signaling contributes to cancer progression and metastatic development. This includes myeloproliferative neoplasms (MPNs) and cutaneous T-cell lymphoma (CTCL). In addition to other cancers in lung, gastric, prostate, colon, cervical, breast...... ^(1,3,5).

(1) Xin P, et al. The role of JAK/STAT signaling pathway and its inhibitors in diseases. Int Immunopharmacol. (2020);80:106210.

(2) Cordes F, et al. Differential regulation of JAK/STAT-signaling in patients with ulcerative colitis and Crohn's disease. World J Gastroenterol. (2020);26(28):4055-4075.

(3) Gutiérrez-Hoya A, & Soto-Cruz I. Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins. Cells. (2020);9(10):2297.

(4) Goker Bagca B, & Biray Avci C.The potential of JAK/STAT pathway inhibition by ruxolitinib in the treatment of COVID-19. Cytokine Growth Factor Rev. (2020);54:51-62.

(5) Shao F, et al. Targeting the JAK/STAT Signaling Pathway for Breast Cancer. Curr Med Chem. (2021);28(25):5137-5151.

JAK-STAT SIGNALING PATHWAY BIOMARKER LIST

You can custom your own SignArrays® with the genes of interest of your choice, according to your project, you just have to download and complete our Personalized SignArrays® information file and send it at [email protected]

You can check the biomarker list included in this pathway, see below:

Species : Homo sapiens (human)

Human signaling pathway

Signaling Pathways	Product ref	Informations
JAK-STAT Signaling Pathway	JAK1H1	List infos

Species : Mus musculus (mouse)

Mouse Signaling Pathway

Signaling Pathways	Product ref	Informations
JAK-STAT Signaling Pathway	JAK1M1	List infos

Species : Rattus norvegicus (rat)

Rat Signaling Pathway

Signaling Pathways	Product ref	Informations
JAK-STAT Signaling Pathway	*******	List In progress...

Species : Sus Scrofa (Pig)

Pig signaling Pathway

Signaling Pathways	Product ref	Informations
JAK-STAT Signaling Pathway	*******	List In progress...

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