title: The molecular regulation of Janus kinase (JAK) activation.
abstract: The JAK (Janus kinase) family members serve essential roles as the intracellular signalling effectors of cytokine receptors. This family, comprising JAK1, JAK2, JAK3 and TYK2 (tyrosine kinase 2), was first described more than 20 years ago, but the complexities underlying their activation, regulation and pleiotropic signalling functions are still being explored. Here, we review the current knowledge of their physiological functions and the causative role of activating and inactivating JAK mutations in human diseases, including haemopoietic malignancies, immunodeficiency and inflammatory diseases. At the molecular level, recent studies have greatly advanced our knowledge of the structures and organization of the component FERM (4.1/ezrin/radixin/moesin)-SH2 (Src homology 2), pseudokinase and kinase domains within the JAKs, the mechanism of JAK activation and, in particular, the role of the pseudokinase domain as a suppressor of the adjacent tyrosine kinase domain's catalytic activity. We also review recent advances in our understanding of the mechanisms of negative regulation exerted by the SH2 domain-containing proteins, SOCS (suppressors of cytokine signalling) proteins and LNK. These recent studies highlight the diversity of regulatory mechanisms utilized by the JAK family to maintain signalling fidelity, and suggest alternative therapeutic strategies to complement existing ATP-competitive kinase inhibitors.
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: Jeffrey J
authors: JJ
authors: Babon
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: Isabelle S
authors: IS
authors: Lucet
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: James M
authors: JM
authors: Murphy
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: Nicos A
authors: NA
authors: Nicola
authors: The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.|Department of Medical Biology, University of Melbourne, Parkville, Victoria 3050, Australia.
authors: Leila N
authors: LN
authors: Varghese
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D004789:Enzyme Activation; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1 / Q000378:metabolism*; D053614:Janus Kinase 2 / Q000378:metabolism*; D053616:Janus Kinase 3 / Q000378:metabolism*; D017493:Leukocyte Common Antigens / Q000378:metabolism; D009196:Myeloproliferative Disorders / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000502:physiology; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000378:metabolism; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11 / Q000378:metabolism; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000378:metabolism; D011506:Proteins / Q000378:metabolism; D018121:Receptors, Cytokine / Q000502:physiology; D015398:Signal Transduction; D053634:TYK2 Kinase / Q000378:metabolism*; D018909:src Homology Domains
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; D018121:Receptors, Cytokine; C490778:SH2B3 protein, human; D053613:Janus Kinase 1; D053614:Janus Kinase 2; D053616:Janus Kinase 3; D053634:TYK2 Kinase; D017493:Leukocyte Common Antigens; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6