JAKs and STATs from a Clinical Perspective: Loss-of-Function Mutations, Gain-of-Function Mutations, and Their Multidimensional Consequences

Abstract

The JAK/STAT signaling pathway plays a key role in cytokine signaling and is involved in development, immunity, and tumorigenesis for nearly any cell. At first glance, the JAK/STAT signaling pathway appears to be straightforward. However, on closer examination, the factors influencing the JAK/STAT signaling activity, such as cytokine diversity, receptor profile, overlapping JAK and STAT specificity among non-redundant functions of the JAK/STAT complexes, positive regulators (e.g., cooperating transcription factors), and negative regulators (e.g., SOCS, PIAS, PTP), demonstrate the complexity of the pathway’s architecture, which can be quickly disturbed by mutations. The JAK/STAT signaling pathway has been, and still is, subject of basic research and offers an enormous potential for the development of new methods of personalized medicine and thus the translation of basic molecular research into clinical practice beyond the use of JAK inhibitors. Gain-of-function and loss-of-function mutations in the three immunologically particularly relevant signal transducers STAT1, STAT3, and STAT6 as well as JAK1 and JAK3 present themselves through individual phenotypic clinical pictures. The established, traditional paradigm of loss-of-function mutations leading to immunodeficiency and gain-of-function mutation leading to autoimmunity breaks down and a more differentiated picture of disease patterns evolve. This review is intended to provide an overview of these specific syndromes from a clinical perspective and to summarize current findings on pathomechanism, symptoms, immunological features, and therapeutic options of STAT1, STAT3, STAT6, JAK1, and JAK3 loss-of-function and gain-of-function diseases.

JAK/STAT Signaling Predominates in Human and Murine Fungal Post-infectious Inflammatory Response Syndrome

“…JAK/STATs are critical bridges linking cytokines and chemokines extracellularly with transcriptional changes intracellularly resulting in immune activation and inflammation (24). In the context of immune control of pathogens, this signaling pathway is vitally important as humans with variants in JAK and STAT family proteins are highly susceptible to infection by a variety of pathogens (25)(26)(27)(28)(29). In response to pathogens and at the molecular level, cytokine stimulation of their cognate receptors leads to JAK kinase activation resulting in the phosphorylation of STATs, which then become activated and translocate as dimers to the nucleus to activate gene transcription.…”

Circulating miRNAs Expression in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Further predicted genes included STAT1 , a gene coding cytokine-induced factors, including interferons (IFNs), EGF, PDGF, and IL-6 [ 60 , 61 ]. STAT1 protein has a crucial role in regulating immune responses to viral, fungal, and mycobacterial pathogens, and its mutation has been associated with pathological immunodeficiency [ 62 ]. In addition, STAT1 has been recognized to be involved in chronic fatigue and immune deficiency syndrome (CFIDS) and can mediate mitochondrial dysfunction by ROS and disruption of ATP production [ 63 ].…”

The oncogenic mechanisms of the Janus kinase-signal transducer and activator of transcription pathway in digestive tract tumors

“…Signal transduction through the JAK-STAT pathway is mediated by four cytosolic JAKs situated near the cell membrane [ 65 , 66 ]. Each JAK can bind to multiple types of cytokine receptors, resulting in different downstream effects [ 67 ]. JAK1, JAK2, and tyrosine kinase 2 are ubiquitously expressed in mammals, whereas the expression of JAK3 is predominantly restricted to hematopoietic, endothelial, and vascular smooth muscle cells [ 58 , 68 – 71 ].…”