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 vital intracellular signaling mechanism that bridges extracellular stimuli, such as cytokines and growth factors, to nuclear responses, influencing gene expression. It regulates critical biological processes like immune responses, cell proliferation, differentiation, angiogenesis, and apoptosis. Dysregulation of this pathway is linked to various diseases, including autoimmune disorders, cancers such as colorectal cancer (CRC), and inflammatory conditions.

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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) .

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).

ACTIVATION OF JAK-STAT PATHWAY

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).

JAK-STAT PATHWAY AND DISEASES

Among the STAT proteins, STAT3 and STAT5 are often persistently activated in various human cancer cell lines and primary cells from cancer patients. These molecules play a key role in the initiation, progression, and survival of cancer cells.

Beyond its pivotal role in cellular signaling, the JAK/STAT pathway is implicated in a wide range of diseases. These include rheumatoid arthritis, Parkinson’s disease, multiple sclerosis, sepsis, inflammatory bowel disease, and COVID-19 infection.

Aberrant activation of the JAK/STAT pathway contributes significantly to cancer progression and metastatic spread. This is particularly evident in myeloproliferative neoplasms (MPNs), cutaneous T-cell lymphoma (CTCL), and a variety of other cancers, including those of the lung, gastric, prostate, colon, cervical, and breast tissues.

CLINICAL APPLICATIONS AND THERAPEUTIC TARGETING

The JAK-STAT pathway's role in disease progression makes it a key target for therapeutic interventions. For instance:

In cancers like CRC, aberrant JAK-STAT signaling drives tumor growth, immune evasion, and treatment resistance. Targeting this pathway can reduce tumor proliferation and enhance sensitivity to therapies.
In inflammatory and autoimmune conditions, JAK inhibitors are effective in modulating overactive immune responses.

Recent advancements highlight promising JAK-STAT inhibitors in clinical trials for leukemia and myeloproliferative disorders, offering hope for better management of these diseases.

(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

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

Species : Homo sapiens (human)

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

Species : Mus musculus (mouse)

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

Species : Rattus norvegicus (rat)

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

Species : Sus Scrofa (Pig)

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

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