Interferons and cytokines play a critical role in immune responses. Over the last years, it has become clear that cytokines and interferons utilize similar mechanisms of intracellular signaling. Binding of these molecules to their specific receptors results in activation of tyrosine kinases of the Jak family, that are in turn responsible for phosphorylation of receptor subunits on specific tyrosines. These phosphorylated tyrosines serve as docking sites for Stat factors, recruiting them to the receptor complex where they will be phosphorylated by Jak kinases. A critical question that has not been addressed is whether in the resting state Stats are maintained in the proximity of the receptors or are free in the cytoplasm. In the previous funding period we proposed that some Stat factors may be constitutively associated to receptor subunits either directly or through adaptor proteins. We demonstrated that Stat2 is directly associated with the beta subunit of the type I interferon receptor even before receptor phosphorylation. However, we have no evidence of the direct association of other Stats with cytokine receptors. We have now cloned an adaptor protein that interacts with the same region of the beta chain of the type I interferon receptor that is responsible for associating indirectly with Stat1. In the current application we will test the hypothesis that this adaptor protein serves as link between the beta chain of the receptor and Stat1. We also propose that this adaptor is responsible for the recruitment of Stat1 to other cytokine receptors, and/or may serve as an adaptor for other Stats. Finally, we will determine whether this adaptor protein recruits other signaling components to the receptor complex or is responsible for the cross-talk between different signaling pathways.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Allergy and Immunology Study Section (ALY)
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Marino, Pamela
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University of Illinois at Chicago
Schools of Medicine
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Sandoval, Raudel; Pilkinton, Mark; Colamonici, Oscar R (2009) Deletion of the p107/p130-binding domain of Mip130/LIN-9 bypasses the requirement for CDK4 activity for the dissociation of Mip130/LIN-9 from p107/p130-E2F4 complex. Exp Cell Res 315:2914-20
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Sandoval, Raudel; Xue, Jiaping; Tian, Xinyong et al. (2006) A mutant allele of BARA/LIN-9 rescues the cdk4-/- phenotype by releasing the repression on E2F-regulated genes. Exp Cell Res 312:2465-75
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Sandoval, Raudel; Xue, Jiaping; Pilkinton, Mark et al. (2004) Different requirements for the cytostatic and apoptotic effects of type I interferons. Induction of apoptosis requires ARF but not p53 in osteosarcoma cell lines. J Biol Chem 279:32275-80
Usacheva, Anna; Tian, Xinyong; Sandoval, Raudel et al. (2003) The WD motif-containing protein RACK-1 functions as a scaffold protein within the type I IFN receptor-signaling complex. J Immunol 171:2989-94
Usacheva, Anna; Sandoval, Raudel; Domanski, Paul et al. (2002) Contribution of the Box 1 and Box 2 motifs of cytokine receptors to Jak1 association and activation. J Biol Chem 277:48220-6
Usacheva, A; Smith, R; Minshall, R et al. (2001) The WD motif-containing protein receptor for activated protein kinase C (RACK1) is required for recruitment and activation of signal transducer and activator of transcription 1 through the type I interferon receptor. J Biol Chem 276:22948-53

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