A family of cytokine-inducible inhibitors of signalling.
Cytokines are secreted proteins that regulate important cellular responses such as proliferation and differentiation. Key events in cytokine signal transduction are well defined: cytokines induce receptor aggregation, leading to activation of members of the JAK family of cytoplasmic tyrosine kinases. In turn, members of the STAT family of transcription factors are phosphorylated, dimerize and increase the transcription of genes with STAT recognition sites in their promoters. Less is known of how cytokine signal transduction is switched off. We have cloned a complementary DNA encoding a protein SOCS-1, containing an SH2-domain, by its ability to inhibit the macrophage differentiation of M1 cells in response to interleukin-6. Expression of SOCS-1 inhibited both interleukin-6-induced receptor phosphorylation and STAT activation. We have also cloned two relatives of SOCS-1, named SOCS-2 and SOCS-3, which together with the previously described CIS form a new family of proteins. Transcription of all four SOCS genes is increased rapidly in response to interleukin-6, in vitro and in vivo, suggesting they may act in a classic negative feedback loop to regulate cytokine signal transduction.
Starr
R
R
The Walter and Eliza Hall Institute for Medical Research, Parkville, Victoria, Australia.
Willson
T A
TA
Viney
E M
EM
Murray
L J
LJ
Rayner
J R
JR
Jenkins
B J
BJ
Gonda
T J
TJ
Alexander
W S
WS
Metcalf
D
D
Nicola
N A
NA
Hilton
D J
DJ
D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D002352:Carrier Proteins; D002454:Cell Differentiation / Q000502:physiology; D003001:Cloning, Molecular; D017124:Conserved Sequence; D050822:Cytokine Receptor gp130; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000502:physiology; D018076:DNA, Complementary; D004268:DNA-Binding Proteins / Q000502:physiology; D004791:Enzyme Inhibitors; D005246:Feedback; D005786:Gene Expression Regulation; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000235:genetics; D015850:Interleukin-6 / Q000502:physiology; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D008562:Membrane Glycoproteins / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008969:Molecular Sequence Data; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000502:physiology; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators / Q000502:physiology; D014157:Transcription Factors; D014407:Tumor Cells, Cultured; D018909:src Homology Domains; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D002352:Carrier Proteins; D050822:Cytokine Receptor gp130; D016207:Cytokines; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D017874:Immediate-Early Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008562:Membrane Glycoproteins; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D011518:Proto-Oncogene Proteins; D012097:Repressor Proteins; D050796:STAT3 Transcription Factor; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D000093242:Interleukin-6 Inhibitors; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; C108944:SOCS1 protein, human; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; C494086:STAT3 protein, human; C491590:Socs1 protein, mouse; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; C507924:JAK2 protein, human; C507926:Jak2 protein, mouse