Regulation of JAKs: Insights Gleaned from the Functional Protein Domains
Since their identification in the early 1990s, many studies have investigated the function of Janus kinases as well as their regulation. It took about 15 years until a first crystal structure of a Janus kinase domain was described and by today the structu
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Abstract
Since their identification in the early 1990s, many studies have investigated the function of Janus kinases as well as their regulation. It took about 15 years until a first crystal structure of a Janus kinase domain was described and by today the structures of all four kinase domains have been explored. In this chapter we discuss the effects of the different JAK domains on the activity, trafficking and localisation of JAKs that were reported in mutagenesis studies in the last 20 years of JAK research. We take into consideration the recently solved crystal structures of the kinase domains as well as other structural information. In addition, we reflect on the lessons that the recently identified activating mutations in patients teach us.
Introduction The family of Janus kinases (JAK) consists of four mammalian members: JAK1, JAK2, JAK3 and TYK2. JAK1, JAK2 and TYK2 are ubiquitously expressed, but expression of JAK3 is confined mainly to cells of the haematopoietic system (Yeh and Pellegrini 1999; Heinrich et al. 2003; Ihle and Kerr 1995). JAK kinases are involved in a variety of biological processes including haematopoiesis and regulation of the immune system. Cytokine receptors bind different JAKs (Heinrich et al. 2003; O’Sullivan et al. 2007; Pestka et al. 2004; Kovanen and Leonard 2004; Hintzen et al. 2008) and the specificity
C. Haan • S. Haan (*) Life Sciences Research Unit, University of Luxembourg, 162A Avenue de la Faı¨encerie, 1511 Luxembourg, Luxembourg e-mail: [email protected] D. Ungureanu • T. Pekkala • O. Silvennoinen Institute of Biomedical Technology, University of Tampere, Tampere, Finland Tampere University Hospital, Tampere, Finland Th. Decker and M. M€ uller (eds.), Jak-Stat Signaling: From Basics to Disease, DOI 10.1007/978-3-7091-0891-8_2, # Springer-Verlag Wien 2012
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of various signalling proteins for phosphotyrosine motifs within this receptor determines the signalling characteristics of the different cytokines. JAKs are constitutively associated via their FERM domain with the membrane proximal region of the type I and type II hematopoietic cytokine receptors and JAKs are absolutely required for downstream signal transduction. Currently there is no structural information of the cytoplasmic domains of the cytokine receptors and the exact mechanism of binding and activation of the JAKs in the receptor complex are largely theoretical. Ligand binding induces conformational changes in the receptor and allows juxtapositioning and transphosphorylation of the activation loop tyrosines in JAKs resulting in enhancement of catalytic activity. Subsequently, tyrosine residues in the receptors become phosphorylated allowing recruitment of SH2 domain containing signalling proteins such as members of the Signal Transducer and Activator of Transcription (STAT) family transcription factors. Phosphorylation plays an important role in regulation of JAK activity. As noted, activation of JAKs in response to cytokine stimulation depends on phosphorylation of the activation loop w
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