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* Department of Pharmacology, University of Illinois, Chicago, IL 60612;
Department of Biochemistry and Molecular, University of Medicine and Dentistry New Jersey, New Jersey Medical School, Newark, NJ 07103; and
Muncie Center for Medical Education, Indiana University School of Medicine, Muncie, IN 47306
The interaction between receptors and kinases of the Janus kinase
(Jak) family is critical for signaling by growth factors, cytokines,
and IFNs. Therefore, the characterization of the domains involved in
these interactions is pivotal not only in understanding kinase
activation but also in the development of drugs that mimic or inhibit
signaling. In this report, we have characterized the domains of Jak1
required to associate with distinct cytokine receptor subunits:
IFN-
R
L, IFN-
R, IL-10R, IL-2R, and IL-4R. We
demonstrate that two regions of Jak1 are necessary for the interaction
with cytokine receptors. First, a common N-terminal region that
includes Jak homology (JH) domain 7 and the first 19 aa of JH6, and,
second, a C-terminal region (JH6–3) that was different for distinct
receptors. The contribution of the two different regions of Jak1 to
cytokine receptor binding was also variable. Deletion of JH7–6
impaired the association of IL-2R and IL-4R chains with Jak1 but
did not have a major impact on the binding of Jak1 to IFN-RL or
IL-10R. Interestingly, regardless of the effect on receptor binding,
removal of JH7–6 completely abrogated kinase activation, indicating
that this domain is required for ligand-driven kinase activation and,
thus, for proper signaling through cytokine
receptors.
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