Contribution of the Box 1 and Box 2 Motifs of Cytokine Receptors
to Jak1 Association and Activation*
Anna
Usacheva
,
Raudel
Sandoval,
Paul
Domanski§,
Sergei V.
Kotenko¶,
Keats
Nelms
,
Mark A.
Goldsmith**, and
Oscar
R.
Colamonici
From the Department of Pharmacology, University of
Illinois, Chicago, Illinois 60612, § Inhibitex Inc.,
Alpharretta, Georgia 30004, the ¶ Department of Biochemistry and
Molecular Biology, University of Medicine and Dentistry New
Jersey-New Jersey Medical School, Newark, New Jersey 07103, the
Immunogenomics Laboratory, John Curtin School of Medical
Research, Canberra City ACT2601, Canberra, Australia, and the
** Gladstone Institute of Virology and Immunology and School
of Medicine, University of California, San Francisco, California
94103
Kinases of the Jak family (Jak1/2/3 and Tyk2)
interact with the membrane proximal domain of different cytokine
receptors and play a critical role in the activation of cytokine and
growth factor signaling pathways. In this report we demonstrate that both the Box 1 and Box 2 motif collaborate in the association and
activation of Jak1 by type I interferons. Mutational analysis of the
chain of type I interferon receptor (IFN
RL/IFNAR2) revealed
that Box 1 plays a more significant role in activation than in the
association with Jak1. On the contrary, the Box 2 motif contributes
more to the association with Jak1 than to kinase activation.
Additionally, the study of the Jak1 binding sites on the IL2 receptor
(IL2R), IFN
R/IFNGR1, and IL10R/IL10R1 chains suggests
that cytokine receptors have two different kinds of interaction with
Jak1. One form of interaction involves the Box 1 and the previously
described Box 2 motif, which we now designate as Box 2A, characterized
by the VEVI and LEVL sequences present in IFNRL/IFNAR2 and
IL2R subunits, respectively. The second form of interaction requires
a motif termed Box 2B, which is present in the IFNR/IFNGR1
(SILLPKS) and IL10R/IL10R1 (SVLLFKK) chains. Interestingly, Box 2B
localizes close to the membrane region (8-10 amino acids from
the membrane) similar to Box 1, whereas Box 2A is more distal (38-58
amino acids from the membrane).
*
This work has been supported by National Institutes of
Health Grants CA55079 and GM54709 (to O. R. C.), GM54351 (to
M. A. G.), and by State of New Jersey Commission of Cancer Research Grant 799-021 (to S. V. K.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
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