Suppressors of cytokine signalling: SOCS.
The mechanism of positive regulation of cytokine signalling pathways has been well investigated, whereas our knowledge of negative regulation is relatively sparse. Here we review recent literature on important negative regulators: the family of suppressors of cytokine signalling, SOCS, consisting of eight members (SOCS-1 to SOCS-7 and CIS) all sharing a central SH2 domain and a C-terminal SOCS box. Expression of CIS, SOCS-1, SOCS-2 and SOCS-3 is induced by various cytokines, and overexpression studies in various cell lines have demonstrated their inhibitory roles. These family members have been implicated in the negative regulation of several pathways, particularly the JAK/STAT pathway, and since this signalling pathway is responsible for their induction, they form part of a classical negative feedback circuit. To date, at least three different modulating mechanisms have been demonstrated: through the SH2 domain they bind to phosphotyrosines on the target protein, leading to inhibition of signal transduction by N-terminal inactivation of JAK, by blocking access of STAT to the receptor sites, or by SOCS box-targeting bound proteins to proteasomal degradation. In gene modification studies in mice, it has been demonstrated that SOCS-1 plays an important role in IFNgamma-regulation and T-cell differentiation, while SOCS-2 seems necessary for normal growth regulation. SOCS-3(-/-) mice die during embryogenesis for a reason still not fully understood, but insufficient control of fetal erythropoiesis or defects in placental development may be involved. The physiological role for the other family members, as well as their molecular regulation mechanisms, remain to be revealed.
Larsen
Lykke
L
Department of Medical Anatomy, University of Copenhagen, Panum Institute, Copenhagen, Denmark.
Röpke
Carsten
C
D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry / Q000502:physiology*; D003546:Cysteine Endopeptidases / Q000378:metabolism; D016207:Cytokines / Q000502:physiology*; D004268:DNA-Binding Proteins; D004920:Erythropoiesis / Q000502:physiology; D006128:Growth / Q000502:physiology; D006801:Humans; D017874:Immediate-Early Proteins / Q000737:chemistry / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000378:metabolism; D009687:Nuclear Proteins / Q000737:chemistry / Q000502:physiology*; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D011499:Protein Processing, Post-Translational; D011506:Proteins / Q000737:chemistry / Q000502:physiology*; D051381:Rats; D018121:Receptors, Cytokine / Q000037:antagonists & inhibitors; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; 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 / Q000502:physiology; D018909:src Homology Domains
D002352:Carrier Proteins; D003546:Cysteine Endopeptidases; D016207:Cytokines; D004268:DNA-Binding Proteins; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009097:Multienzyme Complexes; D009687:Nuclear Proteins; D046988:Proteasome Endopeptidase Complex; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D011506:Proteins; D018121:Receptors, Cytokine; D012097:Repressor Proteins; 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; C108944:SOCS1 protein, human; C106643:SOCS2 protein, human; C106644:SOCS3 protein, human; C473084:SOCS4 protein, human; C472529:SOCS4 protein, mouse; C408990:SOCS5 protein, human; C473085:SOCS6 protein, human; C108775:SOCS7 protein, human; C491590:Socs1 protein, mouse; C491589:Socs1 protein, rat; C491409:Socs2 protein, mouse; C491408:Socs2 protein, rat; C491411:Socs3 protein, mouse; C491410:Socs3 protein, rat; C485811:Socs5 protein, mouse; C473086:Socs6 protein, mouse