Mutational analyses of the SOCS proteins suggest a dual domain requirement but distinct mechanisms for inhibition of LIF and IL-6 signal transduction.
SOCS-1 (suppressor of cytokine signaling-1) is a representative of a family of negative regulators of cytokine signaling (SOCS-1 to SOCS-7 and CIS) characterized by a highly conserved C-terminal SOCS box preceded by an SH2 domain. This study comprehensively examined the ability of several SOCS family members to negatively regulate the gp130 signaling pathway. SOCS-1 and SOCS-3 inhibited both interleukin-6 (IL-6)- and leukemia inhibitory factor (LIF)-induced macrophage differentiation of murine monocytic leukemic M1 cells and LIF induction of a Stat3-responsive reporter construct in 293T fibroblasts. Deletion of amino acids 51-78 in the N-terminal region of SOCS-1 prevented inhibition of LIF signaling. The SOCS-1 and SOCS-3 N-terminal regions were functionally interchangeable, but this did not extend to other SOCS family members. Mutation of SH2 domains abrogated the ability of both SOCS-1 and SOCS-3 to inhibit LIF signal transduction. Unlike SOCS-1, SOCS-3 was unable to inhibit JAK kinase activity in vitro, suggesting that SOCS-1 and SOCS-3 act on the JAK-STAT pathway in different ways. Thus, although inhibition of signaling by SOCS-1 and SOCS-3 requires both the SH2 and N-terminal domains, their mechanisms of action appear to be biochemically different.
Nicholson
S E
SE
The Walter and Eliza Hall Institute of Medical Research and the Cooperative Research Center for Cellular Growth Factors, Parkville, Victoria 3050, Australia. snicholson@wehi.edu.au
Willson
T A
TA
Farley
A
A
Starr
R
R
Zhang
J G
JG
Baca
M
M
Alexander
W S
WS
Metcalf
D
D
Hilton
D J
DJ
Nicola
N A
NA
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002352:Carrier Proteins / Q000737:chemistry / Q000235:genetics* / Q000502:physiology*; D002454:Cell Differentiation; D002460:Cell Line; D016207:Cytokines / Q000502:physiology; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors / Q000502:physiology*; D015850:Interleukin-6 / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases; D053605:Leukemia Inhibitory Factor; D008222:Lymphokines / Q000502:physiology*; D051379:Mice; D020928:Mitogen-Activated Protein Kinases; D009154:Mutation; D010766:Phosphorylation; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D012097:Repressor Proteins; 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; D014157:Transcription Factors; D014162:Transfection; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains / Q000235:genetics
D002352:Carrier Proteins; D016207:Cytokines; D004268:DNA-Binding Proteins; D006131:Growth Inhibitors; D015850:Interleukin-6; D053605:Leukemia Inhibitory Factor; C507838:Lif protein, mouse; D008222:Lymphokines; D011506:Proteins; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; C491409:Socs2 protein, mouse; C491411:Socs3 protein, mouse; 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; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D020928:Mitogen-Activated Protein Kinases