Activation of Janus Kinases During Tumorigenesis
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 t
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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 b 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
J.W. Schmidt Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, DRCII, Rm. 5012, Omaha, NE 68198-5950, USA K.-U. Wagner (*) Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, 985950 Nebraska Medical Center, DRCII, Rm. 5012, Omaha, NE 68198-5950, USA Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA e-mail: [email protected] Th. Decker and M. M€ uller (eds.), Jak-Stat Signaling: From Basics to Disease, DOI 10.1007/978-3-7091-0891-8_15, # Springer-Verlag Wien 2012
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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.
Preface The four members of the Janus kinase family (JAK1, JAK2, TYK2, and JAK3) meditate signaling from multiple hormone and cytokine receptors that are crucial for normal development as well as the initiation and progression of hematopoietic malignancies and solid cancers. This chapter briefly summarizes the main biologically relevant functions of JAKs in normal tissue homeostasis and the mechanisms that mediate an aberrant activation of Janus kinases in human cancers. Also highlighted in this chapter will be the importance of JAKs as components of broader signaling networks, in particular their association to receptor
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