Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P14784 (IL-2 receptor)
 3,849 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Signaling through the hematopoietic receptors requires activation of receptor-associated Janus (Jak) kinases. For example, Jak1 and Jak3 bind specifically to the IL-2 receptor beta (IL-2Rbeta) and common gamma (gammac) chains, respectively, and initiate biochemical signals critical in controlling immune responses. The region of Jak responsible for receptor interactions, however, is not well characterized. Here we describe a naturally occurring Jak3 mutation from a patient with autosomal severe combined immunodeficiency (SCID), where a single amino acid substitution, Y100C, in Janus homology domain 7 (JH7) prevents kinase-receptor interaction. This mutation also results in a loss of IL-2-induced signaling in a B-cell line derived from this patient. Using mutational analysis we have identified a region of Jak3, including portions of JH6 and JH7, that is sufficient for kinase-receptor contact and show that this segment interacts with the proline-rich Box1 region of the receptor. Furthermore, a Jak3-Jak1 chimera containing only the JH6 and JH7 domains of Jak3 interacts with gammac and can reconstitute IL-2-dependent responses, including receptor phosphorylation and activation of signal transducer and activator of transcription (STAT) 5b. Our results suggest that the N-terminus of Jak kinases is critical for receptor binding, and is therefore likely to determine specificity of Jak kinase-receptor interactions.
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PMID:Autosomal SCID caused by a point mutation in the N-terminus of Jak3: mapping of the Jak3-receptor interaction domain. 1007 26

Interleukin-2 induces heterodimerization of the IL-2 receptor beta and gamma subunits. This study addresses a role of the Shb adapter protein in IL-2 receptor signaling in T and NK cells. The IL-2Rbeta and gamma chains were found to co-immunoprecipitate with Shb, when each alone was co-expressed with Shb in COS cells. Using fusion proteins, the Shb SH2 domain was found to associate in a phosphotyrosine-dependent manner with the IL-2 receptor beta and gamma subunits upon IL-2 stimulation in primary T cells and the NK cell line NK-92. The main binding site of the Shb SH2 domain was phosphorylated Tyr-510 in the IL-2Rbeta chain. Shb was also phosphorylated upon IL-2 stimulation when overexpressed together with IL-2Rbeta (in pre-B cells, which express the gamma chain constitutively). These cells were also less apoptotic in the presence of IL-2 than cells overexpressing a mutant Shb (with a defect SH2 domain) or cells expressing a mutant IL-2Rbeta, with the Shb binding sites mutated to phenylalanine (Y392F, Y510F). JAK1 and JAK3 were also found to associate with Shb, but in contrast to the Shb-IL-2 receptor association, JAK1 and 3 appear to associate with the proline-rich regions of Shb. In conclusion, Shb links the IL-2 receptor to other signaling proteins and mediates the regulation of apoptosis in the presence of IL-2.
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PMID:IL-2 receptor signaling through the Shb adapter protein in T and NK cells. 1220 Jan 37