The role of the inhibitors of interleukin-6 signal transduction SHP2 and SOCS3 for desensitization of interleukin-6 signalling.
The immediate early response of cells treated with IL-6 (interleukin-6) is the activation of the signal transducer and activator of transcription (STAT)3. The Src homology domain 2 (SH2)-containing protein tyrosine phosphatase SHP2 and the feedback inhibitor SOCS3 (suppressor of cytokine signalling) are potent inhibitors of IL-6 signal transduction. Impaired function of SOCS3 or SHP2 leads to enhanced and prolonged IL-6 signalling. The inhibitory function of both proteins depends on their recruitment to the tyrosine motif 759 within glycoprotein gp130. In contrast to inactivation, desensitization of signal transduction is regarded as impaired responsiveness due to prestimulation. Usually, after activation the sensing receptor becomes inactivated by modifications such as phosphorylation, internalization or degradation. We designed an experimental approach which allows discrimination between desensitization and inactivation of IL-6 signal transduction. We observed that pre-stimulation with IL-6 renders cells less sensitive to further stimulation with IL-6. After several hours, the cells become sensitive again. We show that not only signal transduction through previously activated receptors is affected by desensitization but signalling through receptors which were not targeted by the first stimulation was also attenuated ( trans -desensitization). Interestingly, in contrast to inhibition, desensitization does not depend on the presence of functional SHP2. Furthermore, cells lacking SOCS3 show constitutive STAT3 activation which is not affected by pre-stimulation with IL-6. All these observations suggest that desensitization and inhibition of signalling are mechanistically distinct.
Fischer
Patrick
P
Department of Biochemistry, Faculty of Medicine, RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
Lehmann
Ute
U
Sobota
Radoslaw M
RM
Schmitz
Jochen
J
Niemand
Claudia
C
Linnemann
Sonja
S
Haan
Serge
S
Behrmann
Iris
I
Yoshimura
Akihiko
A
Johnston
James A
JA
Müller-Newen
Gerhard
G
Heinrich
Peter C
PC
Schaper
Fred
F
D000818:Animals; D015703:Antigens, CD / Q000737:chemistry; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics; D002460:Cell Line; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D007700:Kinetics; D008562:Membrane Glycoproteins / Q000737:chemistry; D051379:Mice; D018345:Mice, Knockout; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases / Q000502:physiology*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D050796:STAT3 Transcription Factor; 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 / Q000378:metabolism; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D014443:Tyrosine / Q000502:physiology; D000093242:Interleukin-6 Inhibitors
D015703:Antigens, CD; D002352:Carrier Proteins; D050822:Cytokine Receptor gp130; D004268:DNA-Binding Proteins; D015850:Interleukin-6; D047908:Intracellular Signaling Peptides and Proteins; D053613:Janus Kinase 1; D008562:Membrane Glycoproteins; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; 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; D014443:Tyrosine; D000093242:Interleukin-6 Inhibitors; C494199:IL6ST protein, human; C494200:Il6st protein, mouse; C108944:SOCS1 protein, human; C106644:SOCS3 protein, human; C494086:STAT3 protein, human; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494087:Stat3 protein, mouse; C507904:JAK1 protein, human; C507905:Jak1 protein, mouse; C516724:PTPN11 protein, human; C516725:Ptpn11 protein, mouse