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JAK-STAT SIGNALING PATHWAY IN DEVELOPMENT AND DISEASES

The JAK-STAT signaling pathway, also called Janus Kinase/Signal Transducer and Activator of Transcription (JAK/STAT), is a fundamental intracellular mechanism that links extracellular stimuli such as cytokines and growth factors to nuclear gene expression. It plays a vital role in immune responses, cell proliferation, differentiation, angiogenesis, and apoptosis.

Dysregulation of this pathway is strongly associated with autoimmune disorders, cancer and inflammatory diseases.

With AnyGenes®’ qPCR arrays, researchers can achieve high sensitivity and specificity in gene expression profiling, enabling the discovery of new therapeutic targets and a deeper understanding of  JAK-STAT signaling mechanisms.

AnyGenes® JAK-STAT Pathway qPCR Array - innovative tool for analyzing gene expression in cytokine and growth factor signaling pathways.

Discover our advanced qPCR arrays for JAK-STAT Pathway research.

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

The schematic structures of the JAK and STAT proteins and overview of the JAK/STAT pathway
AMPK substrates act in specific subcellular locales to rewire metabolism.

 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).

KEY COMPONENTS OF THE JAK-STAT PATHWAY

The pathway is built around several essential elements:

  • Janus Kinase family (JAKs): JAK1, JAK2, JAK3, and TYK2 (tyrosine kinase 2) (non-transmembrane tyrosine kinases).
  • Signal Aransducers and Activators of Transcription (STATs): STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b and STAT6.
  • Cytokines and growth factors (ligands).
  • Cytokines receptors I and II.
  • Regulatory molecules: SOCS (suppressors of cytokines signaling), PIAS (protein inhibitors of activated STAT), and PTPs (protein tyrosine phosphatases).

HOW THE JAK-STAT PATHWAY is activated?

Activation occurs when ligands (cytokines, hormone and growth factor) bind to their receptors, triggering JAK phosphorylation. Once phosphorylated, STATs are recruited, activated, and translocated to the nucleus, where they regulate gene transcription.

In addition, several molecules act as negative regulators of the JAK-STAT pathway. Among them are SOCS, PIAS, and PTPs, which help maintain balance and prevent excessive activation.

JAK-STAT SIGNALING PATHWAY AND DISEASES

Cancer and tumor progression

Persistent activation of STAT3 and STAT5 is observed in many cancers and contributes to tumor growth, survival, and metastasis.

Autoimmune and inflammatory diseases

Aberrant JAK-STAT signaling is linked to autoimmune disorders such as rheumatoid arthritis, multiple sclerosis, and inflammatory bowel disease.

Neurological and infectious diseases

This pathway also plays a role in neurodegenerative disorders like Parkinson’s disease, as well as in infections such as sepsis and COVID-19.

CLINICAL APPLICATIONS AND THERAPEUTIC TARGETING

Because of its central role, the JAK-STAT pathway has become a major therapeutic target.

  • In cancer research, inhibition of JAK/STAT reduces tumor proliferation and improves treatment sensitivity.
  • For autoimmune and inflammatory diseases, JAK inhibitors are widely used to regulate overactive immune responses.
  • In emerging therapies, novel inhibitors are currently in clinical trials for leukemia, myeloproliferative disorders, and other diseases.

Moreover, ongoing research continues to uncover new applications of JAK-STAT targeting in precision medicine.

FREQUENTLY ASKED QUESTIONS

The JAK-STAT pathway transmits signals from cytokines and growth factors to the nucleus, where it regulates gene expression involved in immune response, cell growth, and survival.

Abnormal JAK-STAT activity is associated with autoimmune diseases, cancers, neurodegenerative disorders, and infectious diseases such as COVID-19.

JAK inhibitors are used in the treatment of autoimmune diseases, inflammatory conditions, and some cancers by blocking overactive signaling.

The JAK-STAT pathway follows a well-defined sequence of steps that link extracellular signals to gene regulation:

  • Ligand binding: a cytokine or growth factor binds to its specific receptor on the cell surface.
  • Receptor activation: this binding causes receptor dimerization and activates Janus kinases (JAKs) associated with the receptor.
  • JAK phosphorylation: activated JAKs phosphorylate tyrosine residues on the receptor’s cytoplasmic tail.
  • STAT recruitment: signal transducers and activators of transcription (STATs) are recruited via their SH2 domains to these phosphorylated sites.
  • STAT phosphorylation: JAKs phosphorylate STATs, enabling them to detach from the receptor.
  • STAT dimerization: phosphorylated STATs form homo- or heterodimers.
  • Nuclear translocation: STAT dimers move into the nucleus, where they bind to specific DNA sequences.
  • Gene transcription: STATs regulate the expression of target genes involved in immunity, cell proliferation, differentiation, or apoptosis.
  • Negative regulation: Proteins such as SOCS, PIAS, and PTPs provide feedback control to prevent overactivation.

This stepwise mechanism makes the JAK-STAT pathway one of the most direct signaling cascades, with only a few intermediates between the receptor and the nucleus.

You can check our JAK/STAT biomarker list in the table below to determine if it includes the genes relevant to your study. If not, you can personalize your own SignArrays® by downloading and completing our Personalized SignArrays® information file. Send it to [email protected] to get started on your project.

  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

Customize your own signaling pathways (SignArrays®) with the factors of your choice!
Simply download and complete our Personalized SignArrays® information file and send it at [email protected] to get started on your project.

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

Species : Homo sapiens (human)

Human signaling pathways

Signaling PathwaysProduct refInformations

JAK-STAT Signaling Pathway

JAK1H1

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Species : Mus musculus (mouse)

Mouse Signaling Pathways

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JAK-STAT Signaling Pathway

JAK1M1

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Species : Rattus norvegicus (rat)

Rat Signaling Pathways

Signaling PathwaysProduct refInformations

JAK-STAT Signaling Pathway

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List In progress...


Species : Sus Scrofa (Pig)

Pig signaling Pathways

Signaling PathwaysProduct refInformations

JAK-STAT Signaling Pathway

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List In progress...


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