The Janus kinases (Jaks)

Abstract

The Janus kinase (Jak) family is one of ten recognized families of non-receptor tyrosine kinases. Mammals have four members of this family, Jak1, Jak2, Jak3 and Tyrosine kinase 2 (Tyk2). Birds, fish and insects also have Jaks. Each protein has a kinase domain and a catalytically inactive pseudo-kinase domain, and they each bind cytokine receptors through amino-terminal FERM (Band-4.1, ezrin, radixin, moesin) domains. Upon binding of cytokines to their receptors, Jaks are activated and phosphorylate the receptors, creating docking sites for signaling molecules, especially members of the signal transducer and activator of transcription (Stat) family. Mutations of the Drosophila Jak (Hopscotch) have revealed developmental defects, and constitutive activation of Jaks in flies and humans is associated with leukemia-like syndromes. Through the generation of Jak-deficient cell lines and gene-targeted mice, the essential, nonredundant functions of Jaks in cytokine signaling have been established. Importantly, deficiency of Jak3 is the basis of human autosomal recessive severe combined immunodeficiency (SCID); accordingly, a selective Jak3 inhibitor has been developed, forming a new class of immunosuppressive drugs.

Figure 1

A schematic representation of the primary structure of Janus kinases (Jaks), which are made up of FERM, SH2-like, pseudokinase and kinase domains. An alternative nomenclature for the putative domains is as a series of Janus homology (JH) domains. The FERM domain mediates binding to cytokine receptors. Both the FERM and the pseudokinase domains regulate catalytic activity and appear to interact with the kinase domain. Jaks autophosphorylate at multiple sites (P), including two in the activation loop of the kinase domain, but the precise function of these modifications is just beginning to be understood.

Figure 2

An overview of cytokine signaling. Cytokines bind to homodimeric or heterodimeric receptors, which are constitutively bound to Jaks. Jaks are thought to be activated by a conformational change in the receptor that allows trans- and/or auto-phosphorylation of the two bound Jaks. These in turn phosphorylate the cytokine receptors. Stat proteins bind the phosphorylated receptor chains, allowing the Jaks to phosphorylate the Stats. Phosphorylated Stats form dimers and translocate and accumulate in the nucleus, where they regulate gene expression.