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Titolo:
Peptide insertions in domain 4 of h beta(c), the shared signalling receptor subunit for GM-CSF, IL3 and IL5, induce ligand-independent activation
Autore:
Jones, KL; Bagley, CJ; Butcher, C; Barry, SC; Vadas, MA; DAndrea, RJ;
Indirizzi:
Hanson Ctr Canc Res, Adelaide, SA 5000, Australia Hanson Ctr Canc Res Adelaide SA Australia 5000 elaide, SA 5000, Australia Inst Med & Vet Sci, Div Human Immunol, Adelaide, SA 5000, Australia Inst Med & Vet Sci Adelaide SA Australia 5000 delaide, SA 5000, Australia Univ Adelaide, Dept Med, Adelaide, SA 5005, Australia Univ Adelaide Adelaide SA Australia 5005 ed, Adelaide, SA 5005, Australia
Titolo Testata:
CYTOKINE
fascicolo: 6, volume: 14, anno: 2001,
pagine: 303 - 315
SICI:
1043-4666(20010621)14:6<303:PIID4O>2.0.ZU;2-9
Fonte:
ISI
Lingua:
ENG
Soggetto:
COLONY-STIMULATING FACTOR; COMMON BETA-SUBUNIT; ERYTHROPOIETIN RECEPTOR; IL-5 RECEPTORS; INTERLEUKIN-3 IL-3; CRYSTAL-STRUCTURE; GROWTH-HORMONE; ALPHA-CHAIN; TYROSINE PHOSPHORYLATION; SATURATION MUTAGENESIS;
Keywords:
cytokine receptor; GM-CSF; duplication; mutation; structure;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: D'Andrea, RJ Hanson Ctr Canc Res, Frome Rd, Adelaide, SA 5000, Australia Hanson Ctr Canc Res Frome Rd Adelaide SA Australia 5000 ralia
Citazione:
K.L. Jones et al., "Peptide insertions in domain 4 of h beta(c), the shared signalling receptor subunit for GM-CSF, IL3 and IL5, induce ligand-independent activation", CYTOKINE, 14(6), 2001, pp. 303-315

Abstract

A mutant form of the common beta -subunit of the GM-CSF, interleukin-3 (IL3) and IL5 receptors is activated by a 37 residue duplicated segment which includes the WSXWS motif and an adjacent, highly conserved, aliphatic/basicelement. Haemopoietic expression of this mutant, hp,FIA, in mice leads to myeloproliferative disease. To examine the mechanism of activation of this mutant we targetted the two conserved motifs in each repeat for mutagenesis. Here we show that this mutant exhibits constitutive activity in BaF-B03 cells in the presence of mouse or human GM-CSF receptor alpha -subunit (GMR alpha) and this activity is disrupted by mutations of the conserved motifs in the first repeat. In the presence of these mutations the receptor reverts to an alternative conformation which retains responsiveness to human IL3 in a CTLL cell line co-expressing the human IL3 receptor alpha -subunit (hIL3R alpha). Remarkably, the activated conformation is maintained in the presence of substitutions, deletions or replacement of the second repeat. Thissuggests that activation occurs due to insertion of extra sequence after the WSXWS motif and is not dependent on the length or specific sequence of the insertion. Thus h beta (c) displays an ability to fold into functional receptor conformations given insertion of up to 37 residues in the membrane-proximal region. Constitutive activation most likely results from a specific conformational change which alters a dormant, inactive receptor complex, permitting functional association with GMR alpha and ligand-independent mitogenic signalling. (C) 2001 Academic Press.

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Documento generato il 19/09/20 alle ore 23:18:47