A single amino acid substitution (Trp(666)-->Ala) in the interbox1/2 region of the interleukin-6 signal transducer gp130 abrogates binding of JAK1, and dominantly impairs signal transduction.
gp130 is the common signal-transducing receptor chain of interleukin (IL)-6-type cytokines. Here we describe, for the first time, a single amino acid substitution (Trp(666)-->Ala) in the membrane-proximal interbox1/2 region that abrogates activation of STAT (signal transducer and activator of transcription) transcription factors and the proliferative response of pro-B-cell transfectants. Moreover, association of the Janus kinase JAK1 is prevented. No signalling of heterodimeric IL-5 receptor (IL-5R)/gp130 chimaeras occurs in COS-7 cells, even when only a single cytoplasmic chain of a gp130 dimer contains the Trp(666)Ala mutation, indicating that it acts dominantly.
Haan
C
C
Department of Biochemistry, RWTH Aachen, Pauwelsstr. 30, 52074 Aachen, Germany.
Hermanns
H M
HM
Heinrich
P C
PC
Behrmann
I
I
D000409:Alanine / Q000737:chemistry*; D000818:Animals; D015703:Antigens, CD / Q000737:chemistry* / Q000378:metabolism*; D001402:B-Lymphocytes / Q000378:metabolism; D019556:COS Cells; D002455:Cell Division; D050822:Cytokine Receptor gp130; D003593:Cytoplasm / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D015850:Interleukin-6 / Q000378:metabolism*; D053613:Janus Kinase 1; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000378:metabolism*; D051379:Mice; D016297:Mutagenesis, Site-Directed; D017354:Point Mutation; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000737:chemistry* / Q000378:metabolism*; D018123:Receptors, Interleukin / Q000378:metabolism; D053649:Receptors, Interleukin-5; D015398:Signal Transduction; D015533:Transcriptional Activation; D014162:Transfection; D014364:Tryptophan / Q000737:chemistry*
D015703:Antigens, CD; C494200:Il6st protein, mouse; D015850:Interleukin-6; D008562:Membrane Glycoproteins; D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5; D050822:Cytokine Receptor gp130; D014364:Tryptophan; D011505:Protein-Tyrosine Kinases; C507905:Jak1 protein, mouse; D053613:Janus Kinase 1; D000409:Alanine