Heterodimerization of the IL-2 receptor β- and γ-chain cytoplasmic domains is required for signalling

Nakamura, Yoki; Russell, Sarah M.; Mess, Sarah A.; Friedmann, Michael; Erdos, Michael R.; François, Christine; Jacques, Yannick; Adelstein, Stephen; Leonard, Warren J.

doi:10.1038/369330a0

Cited by 312 publications

(175 citation statements)

References 28 publications

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“…Dimerization of IL-2R␤ and ␥ c was previously shown to be essential for transducing IL-2-induced signals (28,44). We now demonstrate that in COS-7 cells, which constitutively express endogenous Jak1, we can reconstitute IL-2-induced Stat5 activation by transfecting Jak3 in addition to receptor chains, Stat5A, and/or Stat5B.…”

Section: Isolation Of Two Closely Related Human Stat5 Cdnas Whosesupporting

confidence: 52%

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Cloning of Human Stat5B

Lin

Mietz

Modi

et al. 1996

Journal of Biological Chemistry

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196

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We have isolated a second human Stat5 cDNA, Stat5B, and demonstrated that the genes encoding both Stat5A and Stat5B are located at chromosome 17q11.2. Both genes were constitutively transcribed in peripheral blood lymphocytes. By using specific antisera, we demonstrated that both Stat5A and Stat5B are activated by interleukin-2 (IL-2) in peripheral blood lymphocytes, natural killer-like YT leukemia cells, and human T cell lymphotropic virus type I-transformed MT-2 T cells. In COS-7 cells, which constitutively express the Janus family tyrosine kinase Jak1, reconstitution of IL-2-induced Stat5A and Stat5B DNA binding activities was dependent on the coexpression of Jak3 along with the IL-2 receptor ␤ chain and the common cytokine receptor ␥-chain. This IL-2-induced Stat5 activation was dependent on the presence of either of two tyrosines (Tyr-392 or Tyr-510) in the IL-2 receptor ␤ chain, indicating that either of these two tyrosines can serve as a docking site. Moreover, we demonstrated that human Stat5 activation is also dependent on Tyr-694 in Stat5A and Tyr-699 in Stat5B, indicating that these tyrosines are required for dimerization. The COS-7 reconstitution system described herein provides a valuable assay for further elucidation of the IL-2-activated JAK-STAT pathway.

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Section: Isolation Of Two Closely Related Human Stat5 Cdnas Whosesupporting

confidence: 52%

“…Plasmids, in Vitro Transcription/Translation, and Site-directed Mutagenesis-Human IL-2R␤, ␥ c , and Jak3 cDNAs were subcloned in pME18S (11,28); murine Jak1 was subcloned in pMLCMV. The IL-2R␤ tyrosine mutants were prepared as described (29).…”

Section: Methodsmentioning

confidence: 99%

Cloning of Human Stat5B

Lin

Mietz

Modi

et al. 1996

Journal of Biological Chemistry

Self Cite

196

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“…Therefore, TLR1 and TLR2 are coexpressed in normal human monocytes. However, we cannot exclude the possibility that, as occurs with components of several multichain cytokine receptor families (18,44), TLR1 interacts functionally with other molecules as well. Study of the phenotype of mice with targeted deletions of TLR1 will help resolve this issue.…”

Section: Discussionmentioning

confidence: 99%

Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses

Wyllie

Kiss-Tóth

Visintin

et al. 2000

The Journal of Immunology

245

151

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Members of the Toll-like receptor (TLR) family are components of the mammalian anti-microbial response, signaling with a domain closely related to that of IL-1 receptors. In this report the expression and function of TLR1, a TLR of unknown function, are examined. TLR1 is expressed by monocytes, as demonstrated using a novel mAb. Monocytes also express TLR2. TLR1 transfection of HeLa cells, which express neither TLR1 nor TLR2, was not sufficient to confer responsiveness to several microbial extracts. However, cotransfection of TLR1 and TLR2 resulted in enhanced signaling by HeLa cells to soluble factors released from Neisseria meningitidis relative to the response with either TLR alone. This phenomenon was also seen with high concentrations of some preparations of LPS. The N. meningitidis factors recognized by TLR1/TLR2 were not released by N. meningitidis mutant in the LpxA gene. Although LpxA is required for LPS biosynthesis, because cooperation between TLR1 and TLR2 was not seen with all LPS preparations, the microbial component(s) TLR1/2 recognizes is likely to be a complex of LPS and other molecules or a compound metabolically and chemically related to LPS. The functional IL-1R consists of a heterodimer; this report suggests a similar mechanism for TLR1 and TLR2, for certain agonists. These data further suggest that mammalian responsiveness to some bacterial products may be mediated by combinations of TLRs, suggesting a mechanism for diversifying the repertoire of Toll-mediated responses.

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“…The b-and g-chains are members of the cytokine receptor superfamily due to conserved extracellular and intracellular sequence motifs [4]. Signalling by the IL-2R complex is thought to be mediated by ligand-induced heterodimerization of the cytoplasmic domains of b-and g-chains [5,6]. The mature form of the mouse IL-2Rg is 347 amino acids (aa) long, of which 233 aa form the extracellular, 29 aa the membrane spanning and 85 aa the cytoplasmic region, compared to 232 aa, 29 aa and 86 aa for the human common gamma chain, respectively [7].…”

Section: Introductionmentioning

confidence: 99%

Expression of the Mouse Interleukin‐2 Receptor Gamma Chain in Insect Cells Using a Baculovirus Expression Vector—Comparison with the Human Common Gamma Chain

Stenroos¹,

West²,

Raivio³

et al. 1997

Scand J Immunol

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The gene encoding the γ‐chain of the mouse Interleukin‐2 receptor was expressed in lepidopteran insect cells using the baculovirus expression vector system. The corresponding gene was inserted under the polyhedrin promoter of the Autographa californica nuclear polyhedrosis virus and expressed in the Spodoptera frugiperda insect cell line Sf9 during viral infection. The recombinant receptor protein was identified by immunoblotting in cell lysates prepared from insect cells infected with the produced recombinant virus VL1392‐mIL‐2Rγ. Kinetic analysis demonstrated that the corresponding protein could be detected as an ≈50 kDa protein already at 24 h post‐infection. Intrinsic labelling with [35S]‐methionine/cysteine and SDS‐PAGE analysis of the recombinant baculovirus infected insect cells verified the immunoblotting data. The expressed IL‐2Rγ protein could also be determined on the surface of infected insect cells by flow cytometric analysis. Comparison of the molecular weights between baculovirus expressed human and mouse IL‐2Rγ chains indicated differences in the glycosylation pattern despite similar numbers of N‐linked glycosylation sites.

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Heterodimerization of the IL-2 receptor β- and γ-chain cytoplasmic domains is required for signalling

Cited by 312 publications

References 28 publications

Cloning of Human Stat5B

Cloning of Human Stat5B

Evidence for an Accessory Protein Function for Toll-Like Receptor 1 in Anti-Bacterial Responses

Expression of the Mouse Interleukin‐2 Receptor Gamma Chain in Insect Cells Using a Baculovirus Expression Vector—Comparison with the Human Common Gamma Chain

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