Journal article
Suppression of Cytokine Signaling by SOCS3: Characterization of the Mode of Inhibition and the Basis of Its Specificity
JJ Babon, NJ Kershaw, JM Murphy, LN Varghese, A Laktyushin, SN Young, IS Lucet, RS Norton, NA Nicola
Immunity | Published : 2012
Abstract
Janus kinases (JAKs) are key effectors in controlling immune responses and maintaining hematopoiesis. SOCS3 (suppressor of cytokine signaling-3) is a major regulator of JAK signaling and here we investigate the molecular basis of its mechanism of action. We found that SOCS3 bound and directly inhibited the catalytic domains of JAK1, JAK2, and TYK2 but not JAK3 via an evolutionarily conserved motif unique to JAKs. Mutation of this motif led to the formation of an active kinase that could not be inhibited by SOCS3. Surprisingly, we found that SOCS3 simultaneously bound JAK and the cytokine receptor to which it is attached, revealing how specificity is generated in SOCS action and explaining wh..
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Awarded by National Cancer Institute
Funding Acknowledgements
We thank S. Yao for assistance with NMR, A. Bullock for plasmids, J.-G. Zhang for recombinant IL-6, and the ACRF Biomolecular Resource Facility for sequencing. We are grateful to P. Hertzog for the gift of U4A cells. This work was supported in part by the National Health and Medical Research Council of Australia (program grant nos. 461219 and 487922 and project grant no. 1011804), the U.S. National Institutes of Health (grant no. CA22556), the Victorian State Government Operational Infrastructure Support Grant, and the NHMRC Independent Research Institutes Infrastructure Support Scheme (361646). J.J.B., R.S.N., and N.A.N. acknowledge fellowship support from the National Health and Medical Research Council, and J.M.M. from the Australian Research Council. L.N.V. acknowledges scholarship support from the Leukaemia Foundation of Australia and the Australian Stem Cell Centre. N.A.N. is a founder and member of the scientific advisory board of MuriGen Pty Ltd.