Activation of Janus Kinases during tumorigenesis

Jeffrey W. Schmidt, Kay Uwe Wagner

Research output: Chapter in Book/Report/Conference proceedingChapter

3 Scopus citations

Abstract

Janus tyrosine kinases (JAKs) are important for the growth and homeostasis of a variety of normal tissues. Specifically, JAK1 and JAK2 are essential for mammalian development, and conventional knockout models in mice show that the absence of just one of these two kinases causes prenatal and postnatal lethality. Recent studies using JAK2 conditional knockout mice show that this tyrosine kinase plays key roles in mammary gland development, fertility, pancreatic β cell homeostasis, and the suppression of fatty liver disease in adult animals. Somatically acquired point mutations or structural abnormalities in the JAK2 gene contribute to various hematopoietic malignancies. In contrast, a sustained activation of JAK1 and JAK2 in solid human cancers, such as those of the breast, prostate, lung, head and neck, skin, and gastrointestinal tract, is caused mainly by alternative mechanisms. These include the epigenetic silencing of negative regulators of JAKs as well as an aberrant autocrine stimulation of growth factors such as PRL, EPO, and IL-6. In addition to the canonical pathway through Signal Transducers and Activators of Transcription (STATs), JAKs are an integral part of a crosstalk with receptor tyrosine kinases and their substrates that promote the progression of solid cancers. The biological significance of JAKs within wider signaling networks, however, depends on the cell type and the stage of neoplastic progression. For example, recent studies in breast cancer models that are conditionally deficient in JAK2 show that the importance of this kinase changes during disease initiation and progression, which may have significant implications for targeting this Janus kinase in a chemopreventive or therapeutic setting.

Original languageEnglish (US)
Title of host publicationJak-Stat Signaling
Subtitle of host publicationFrom Basics to Disease
PublisherSpringer-Verlag Vienna
Pages259-288
Number of pages30
ISBN (Electronic)9783709108918
ISBN (Print)9783709108901
DOIs
StatePublished - Jan 1 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Schmidt, J. W., & Wagner, K. U. (2012). Activation of Janus Kinases during tumorigenesis. In Jak-Stat Signaling: From Basics to Disease (pp. 259-288). Springer-Verlag Vienna. https://doi.org/10.1007/978-3-7091-0891-8_15