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Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
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JAK: Not Just Another Kinase.

Ruchi P Agashe1, Scott M Lippman2, Razelle Kurzrock3,4

  • 1Yale University, New Haven, Connecticut.

Molecular Cancer Therapeutics
|October 17, 2022
PubMed
Summary
This summary is machine-generated.

The Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway is crucial in immunity and cancer. JAK inhibitors (jakinibs) show promise in treating various inflammatory diseases and cancers by modulating this signaling axis.

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Area of Science:

  • Immunology and Cancer Biology
  • Molecular Signaling Pathways
  • Pharmacology

Background:

  • The Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway is integral to cellular communication, regulating immune responses, cell growth, and differentiation.
  • Dysregulation of the JAK/STAT axis, through mutations or polymorphisms in JAK family members, is linked to various diseases, including autoimmune disorders, immunodeficiencies, and hematologic malignancies.

Purpose of the Study:

  • To review the multifaceted roles of the JAK/STAT pathway in health and disease.
  • To explore the therapeutic potential of Janus kinase inhibitors (jakinibs) across a spectrum of conditions characterized by JAK/STAT pathway activation.

Main Methods:

  • Literature review of studies on JAK/STAT signaling, associated diseases, and JAK inhibitor therapies.
  • Analysis of clinical trial data and approved indications for jakinibs.
  • Examination of genetic alterations (mutations, polymorphisms, copy-number loss) affecting JAK family members.

Main Results:

  • Germline JAK mutations/polymorphisms correlate with diseases like lupus erythematosus, severe combined immunodeficiency, and hereditary thrombocytosis.
  • Somatic JAK mutations are prevalent in hematologic malignancies, with JAK2 V617F being a hallmark of myeloproliferative disorders.
  • JAK inhibitors are approved for myeloproliferative disorders, inflammatory conditions, and COVID-19, with ongoing trials for other autoimmune diseases.

Conclusions:

  • The JAK/STAT pathway is a critical target for therapeutic intervention in a wide range of immune and malignant disorders.
  • Janus kinase inhibitors (jakinibs) represent a significant advancement in treating diseases driven by aberrant JAK/STAT signaling, with expanding applications in autoimmune and inflammatory conditions.