Shared gamma(c) subunit within the human interleukin-7 receptor complex. A molecular basis for the pathogenesis of X-linked severe combined immunodeficiency.

Lai, Stephen Y.; Molden, Jaime; Goldsmith, Mark A.

doi:10.1172/jci119144

Cited by 41 publications

(23 citation statements)

References 67 publications

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“…The second receptor subunit does not contribute significantly to the specificity of signal transduction but rather triggers receptor activation. This structure/ function arrangement applies to several members of the receptor family which share the ␥ c chain as a trigger chain (55)(56)(57). The present findings indicate that signaling through the homodimeric EPOR is governed by similar structure/function principles.…”

Section: Discussionmentioning

confidence: 55%

Oligomerization and Scaffolding Functions of the Erythropoietin Receptor Cytoplasmic Tail

Watowich¹,

Liu²,

Xie³

et al. 1999

Journal of Biological Chemistry

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Signal transduction by the erythropoietin receptor (EPOR) is activated by ligand-mediated receptor homodimerization. However, the relationship between extracellular and intracellular domain oligomerization remains poorly understood. To assess the requirements for dimerization of receptor cytoplasmic sequences for signaling, we overexpressed mutant EPORs in combination with wild-type (WT) EPOR to drive formation of heterodimeric (i.e. WT-mutant) receptor complexes. Dimerization of the membrane-proximal portion of the EPOR cytoplasmic region was found to be critical for the initiation of mitogenic signaling. However, dimerization of the entire EPOR cytoplasmic region was not required. To examine this process more closely, we generated chimeras between the intracellular and transmembrane portions of the EPOR and the extracellular domains of the interleukin-2 receptor ␤ and ␥ c chains. These chimeras allowed us to assess more precisely the signaling role of each receptor chain because only heterodimers of WT and mutant receptor chimeras form in the presence of interleukin-2. Coexpression studies demonstrated that a functional receptor complex requires the membrane-proximal region of each receptor subunit in the oligomer to permit activation of JAK2 but only one membrane-distal tail to activate STAT5 and to support cell proliferation. Thus, this study defines key relationships involved in the assembly and activation of the EPOR signal transduction complex which may be applicable to other homodimeric cytokine receptors. Erythropoietin (EPO)1 is essential for the survival, proliferation, and terminal differentiation of erythroid progenitor cells (1-3). The erythropoietin receptor (EPOR) belongs to the cytokine receptor superfamily and as such contains the structural motifs of four cysteine residues with canonical spacing and the sequence WSXWS in the extracellular domain (4, 5). Although protein tyrosine phosphorylation is required for cytokine signaling (6), the cytoplasmic regions of these receptors lack intrinsic enzymatic activity. Signal transduction instead is mediated by cytoplasmic protein tyrosine kinases of the JAK family (7). These kinases are constitutively associated with receptor chains; residues in the membrane-proximal region of the EPOR cytoplasmic tail are required for this association. Ligand binding results in homodimerization of EPOR chains, which is critical for the initiation of intracellular signaling (8 -12).The role of homodimerization in the initiation of signaling is highlighted by constitutively active variants of the EPOR chain (10, 13). In the three mutants described to date, R129C, E132C, and E133C, amino acids in the extracellular domain are replaced by cysteines, leading to the formation of intermolecular disulfide bridges and constitutive signaling. In contrast, a number of other cytokine receptors signal through the heterodimerization of asymmetric receptor chains. For example, interleukin-2 (IL-2) binds and heterodimerizes the IL-2R␤ and ␥ c receptor chains (for review, see Refs. 14...

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Section: Discussionmentioning

confidence: 55%

Oligomerization and Scaffolding Functions of the Erythropoietin Receptor Cytoplasmic Tail

Watowich¹,

Liu²,

Xie³

et al. 1999

Journal of Biological Chemistry

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“…28 The IL-7R complex consists of the IL-7R alpha chain and the common cytokine-receptor gamma chain (CD132); the former molecule transduces transmembrane signals through the recruitment of intracellular messengers to its cytoplasmic tail, while the latter activates this transduction. 27,29 IL-7Ra is expressed on immature B cells and T cells; in mice, administration of neutralizing antibodies or genetic ablation of IL7-Ra blocks lymphocyte development. 28 In humans, germline mutations resulting in defective expression of IL-7R give rise to a subtype of the disorder severe combined immunodeficiency.…”

Section: Discussionmentioning

confidence: 99%

Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis

et al. 2005

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Multiple sclerosis (MS) is a T-cell-mediated disease of the central nervous system, characterized by damage to myelin and axons, resulting in progressive neurological disability. Genes may influence susceptibility to MS, but results of association studies are inconsistent, aside from the identification of HLA class II haplotypes. Whole-genome linkage screens in MS have both confirmed the importance of the HLA region and uncovered non-HLA loci that may harbor susceptibility genes. In this twostage analysis, we determined genotypes, in up to 672 MS patients and 672 controls, for 123 single-nucleotide polymorphisms (SNPs) in 66 genes. Genes were chosen based on their chromosomal positions or biological functions. In stage one, 22 genes contained at least one SNP for which the carriage rate for one allele differed significantly (Po0.08) between patients and controls. After additional genotyping in stage two, two genes-each containing at least three significantly (Po0.05) associated SNPs-conferred susceptibility to MS: LAG3 on chromosome 12p13, and IL7R on 5p13. LAG3 inhibits activated T cells, while IL7R is necessary for the maturation of T and B cells. These results imply that germline allelic variation in genes involved in immune homeostasis-and, by extension, derangement of immune homeostasis-influence the risk of MS.

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“…56 Indeed, in a chimeric receptor system, an erythropoietin receptor containing Jak2 can substitute for ␥c-associated Jak3. 57 Thus, IL-7R␣ appears to function as the driver of signaling once activated by dimerization with an appropriate receptor containing a trigger, which in the native setting involves ␥c.…”

Section: Il-7 Receptor and Signalingmentioning

confidence: 99%

Interleukin-7: from bench to clinic

Fry

Mackall

2002

Blood

448

358

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Shared gamma(c) subunit within the human interleukin-7 receptor complex. A molecular basis for the pathogenesis of X-linked severe combined immunodeficiency.

Cited by 41 publications

References 67 publications

Oligomerization and Scaffolding Functions of the Erythropoietin Receptor Cytoplasmic Tail

Oligomerization and Scaffolding Functions of the Erythropoietin Receptor Cytoplasmic Tail

Two genes encoding immune-regulatory molecules (LAG3 and IL7R) confer susceptibility to multiple sclerosis

Interleukin-7: from bench to clinic

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