Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family.

Murakami, Masaaki; Narazaki, Masashi; Hibi, Masahiko; Yawata, Hideo; Yasukawa, Kiyoshi; Hamaguchi, Michinari; Taga, Tetsuya; Kishimoto, Tadamitsu

doi:10.1073/pnas.88.24.11349

Cited by 529 publications

(357 citation statements)

References 34 publications

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“…Box 1, a proline-rich region encompassing residues 245-250 in rat PRLR, is the most highly conserved feature within the cytoplasmic domain of cytokine receptors (26). Interestingly, our study did not identify Box 1 as an internalization signal.…”

Section: Residuesmentioning

confidence: 47%

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Identification of Cytoplasmic Motifs Required for Short Prolactin Receptor Internalization

Vincent

Goffin

Rozakis-Adcock

et al. 1997

Journal of Biological Chemistry

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Cloning of rat prolactin receptor (PRLR) cDNAs revealed the existence of two isoforms, termed short and long according to the length of their cytoplasmic domain. Internalization studies show, first, that PRLR internalization is hormone-dependent and, second, that ligand-receptor complexes of the short PRLR are internalized to a larger extent compared to the long form. In order to identify regions within the cytoplasmic domain of the short PRLR required for efficient internalization, serial truncations of the cytoplasmic tail were performed by inserting a stop codon in place of those encoding residues 282, 273, 262, 253, 244, or 237 (wild type short PRLR contains 291 amino acids). Our data show that two motifs, lying within residues 253-261 and 273-281, are involved in internalization. Both regions contain a consensus feature identified within other receptors as internalization signals, namely a di-leucine peptide (amino acids 259 -260) and a tetrapeptide predicted to adopt a ␤-turn structure (amino acids 276 -279). We propose these two motifs are involved in PRLR endocytosis. Finally, we show that ␣-adaptin, a component of adaptor protein AP-2, coprecipitates with short PRLR complexes upon PRL stimulation, which strongly suggests that PRLR internalization is mediated by the clathrin-coated pits endocytotic pathway.

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Section: Residuesmentioning

confidence: 47%

“…25). Mutational analyses of PRLR, as well as of several members of the PRL/GH/cytokine receptor superfamily, have shown that the membrane-proximal region, which includes a proline-rich motif termed Box 1 (26), is essential for signal transduction, since it mediates receptor association with Janus kinases (for review, see Refs. 25 and 27).…”

mentioning

confidence: 99%

Identification of Cytoplasmic Motifs Required for Short Prolactin Receptor Internalization

Vincent

Goffin

Rozakis-Adcock

et al. 1997

Journal of Biological Chemistry

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“…SIRPα1 also contains a proline-rich motif that conforms to the proline-rich box 1 region of cytokine receptors. The proline-rich region in the cytokine receptors mediates the association between the JAK kinases and the cytokine receptors (23,24,28). Deletion of the proline-rich region of SIRPα1 or proline to alanine mutation of conserved prolines in this region had no effect upon the association of JAK2 with SIRPα1.…”

Section: Discussionmentioning

confidence: 99%

Negative Regulation of Growth Hormone Receptor/JAK2 Signaling by Signal Regulatory Protein α

Stofega

Argetsinger²,

Wang³

et al. 2000

Journal of Biological Chemistry

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SUMMARYSIRPs (signal regulatory proteins) are receptor-like transmembrane proteins, the majority of which contain a cytoplasmic proline-rich region and four cytoplasmic tyrosines that, when phosphorylated, bind SH2 domain-containing protein tyrosine phosphatases (SHP). We Consistent with reduced JAK2 activity, overexpression of wild-type SIRPα1 but not SIRP 4YF reduces GH-induced phosphorylation of ERKs 1 and 2, STAT3 and STAT5B. These results suggest that SIRPα1 is a negative regulator of GH signaling and that the ability of SIRPα1

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“…Growth of transfected BAF ± B03 pro-B cells needed the contribution of both signals derived from gp130: STATs induced anti-apoptotic factors, whereas MAP kinase activation was necessary for proliferation . Short-term DNA synthesis in these cells, however, had even been observed with a truncated gp130 lacking all tyrosine residues required for SHP-2 and STAT activation (Murakami et al, 1991).…”

Section: Introductionmentioning

confidence: 94%

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

Heinrich²,

et al. 1999

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Interleukin-6 (IL-6)-type cytokines lead to growth arrest of human A375 melanoma cells. The present study demonstrates that this e ect depends on the activation of STAT transcription factors. We observed a correlation between the extent of growth inhibition exerted by IL-6, IL-6 plus soluble IL-6 receptor or oncostatin M (OSM) and the intensities of STAT3 and STAT1 signals. A truncated chimeric receptor retaining only the membrane-proximal region of gp130, the common signal transducer of IL-6-type cytokines, did neither activate STATs nor mediate growth arrest of stable transfectants. These functions were restored by the addition of short STAT recruitment modules comprising critical tyrosine residues from gp130 (Y767, Y814). A receptor carrying tyrosine module Y759 of gp130 e ectively mediated activation of the phosphatase SHP-2 but did not alter cell growth. Overexpression of dominant negative forms of STAT3 but not STAT1 abrogated the inhibitory e ect of OSM and IL-6 in A375 cells. In addition, we have identi®ed the cyclin-dependent kinase inhibitor p27/Kip1 as a novel target to be regulated by IL-6-type cytokines. Stimulation-dependent upregulation of p27 mRNA occurred STAT3-dependently. Also p27 protein accumulated which coincided with the disappearance of hyperphosphorylated retinoblastoma protein in three human melanoma cell lines sensitive to IL-6-type cytokines.

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Critical cytoplasmic region of the interleukin 6 signal transducer gp130 is conserved in the cytokine receptor family.

Cited by 529 publications

References 34 publications

Identification of Cytoplasmic Motifs Required for Short Prolactin Receptor Internalization

Identification of Cytoplasmic Motifs Required for Short Prolactin Receptor Internalization

Negative Regulation of Growth Hormone Receptor/JAK2 Signaling by Signal Regulatory Protein α

Interleukin-6 and oncostatin M-induced growth inhibition of human A375 melanoma cells is STAT-dependent and involves upregulation of the cyclin-dependent kinase inhibitor p27/Kip1

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