Janus kinase 3: the controller and the controlled

Abstract

Janus kinase (JAK)-signal transducer and activators of transcription (STAT) signaling pathways play crucial roles in lymphopoiesis. In particular, JAK3 has unique functions in the lymphoid system such that JAK3 ablation results in phenotypes resembling severe combined immunodeficiency syndrome. This review focuses on the biochemistry, immunological functions, and clinical significance of JAK3. Compared with other members of the JAK family, the biochemical properties of JAK3 are relatively less well characterized and thus largely inferred from studies of JAK2. Furthermore, new findings concerning the cross-talks between Notch and JAK signaling pathways through ubiquitin-mediated protein degradation are discussed in more detail.

Figure 1

Domain structure of Janus kinases (JAKs) JAK proteins have four distinct domains, consisting of FERM, SH2-like, pseudo-kinase, and kinase domains. An alternative nomenclature for the putative domains is as seven defined regions of homology called Janus homology (JH) domains 1–7. The FERM domain is responsible for binding to cytokine receptors. Both the FERM and the pseudo-kinase domains regulate catalytic kinase activity and appear to interact with the kinase domain.

Figure 2

A model for the mechanism underlying Notch-promoted JAK3 degradation Notch signaling activates the transcription of Asb2 and Skp2 genes. Both Asb2 and Skp2 interact with JAK3 and they also bind to each other to mediate the formation of a non-canonical heterodimeric E3 ligase complex, containing Cul1 and Cul5 and their associates to catalyze ubiquitination reactions.