_enti_e7
_enti_e8
_enti_e9
_enti_e1
_enti_e10
_enti_e2
_enti_e3
_enti_e4
_enti_e55
_enti_e53
_enti_e59
_enti_e54
_enti_e52
_enti_e51
_enti_e56
_enti_e50
_enti_e61
_enti_e58
_enti_e57
_enti_e62
_enti_e60
g1_fact_g1
g2_fact_g12
g2_fact_g13
g1_fact_g14
p1_propro_p1
PMID: 14644140,9129017,10585430
The SH2 domain of the CIS associates with
STAT5-binding sites of various types of receptor, including
growth hormone (GH) receptors and EPO receptors
c1 cso30:c:InputProcess connector
c3 cso30:c:InputProcess connector
c80 cso30:c:OutputProcess connector
p1_propro_p2
PMID: 14644140,9129017,10585430
The SH2 domain of the CIS associates with
STAT5-binding sites of various types of receptor, including
growth hormone (GH) receptors and EPO receptors
PMID: 14644140,7796808
Initial in vitro studies reported
CIS as an inhibitor of the signal transduction of EPO,
interleukin-2 (IL-2), IL-3, GH and prolactin, by masking
the STAT5-binding sites of receptors and inhibiting
the activation of STAT5.
c4 cso30:c:InputProcess connector
c5 cso30:c:InputProcess connector
c6 cso30:c:InputProcess connector
c88 cso30:c:OutputProcess connector
p3_propro_p3
PMID: 14644140,7796808
Initial in vitro studies reported
CIS as an inhibitor of the signal transduction of EPO,
interleukin-2 (IL-2), IL-3, GH and prolactin, by masking
the STAT5-binding sites of receptors and inhibiting
the activation of STAT5.
c7 cso30:c:InputProcess connector
c9 cso30:c:InputProcess connector
c8 cso30:c:OutputProcess connector
p3_propro_p4
PMID: 14644140,7796808
Initial in vitro studies reported
CIS as an inhibitor of the signal transduction of EPO,
interleukin-2 (IL-2), IL-3, GH and prolactin, by masking
the STAT5-binding sites of receptors and inhibiting
the activation of STAT5.
c10 cso30:c:InputProcess connector
c12 cso30:c:OutputProcess connector
c11 cso30:c:OutputProcess connector
p3_propro_p5
PMID: 14644140,7796808
Initial in vitro studies reported
CIS as an inhibitor of the signal transduction of EPO,
interleukin-2 (IL-2), IL-3, GH and prolactin, by masking
the STAT5-binding sites of receptors and inhibiting
the activation of STAT5.
c13 cso30:c:InputProcess connector
c15 cso30:c:InputProcess connector
c14 cso30:c:OutputProcess connector
p6_propro_p6
PMID: 14644140,10453004,11390452,12433365,12433373,11208867
However, SOCS-1 expression is now known to be
induced by insulin, lipopolysaccharide (LPS), CpG DNA
and other molecules that do not use STATs in signal
transduction
c16 cso30:c:InputAssociation connector
c17 cso30:c:OutputProcess connector
p6_propro_p7
PMID: 14644140,10453004,11390452,12433365,12433373,11208867
However, SOCS-1 expression is now known to be
induced by insulin, lipopolysaccharide (LPS), CpG DNA
and other molecules that do not use STATs in signal
transduction
c18 cso30:c:InputAssociation connector
c19 cso30:c:OutputProcess connector
p6_propro_p8
PMID: 14644140,10453004,11390452,12433365,12433373,11208867
However, SOCS-1 expression is now known to be
induced by insulin, lipopolysaccharide (LPS), CpG DNA
and other molecules that do not use STATs in signal
transduction
c20 cso30:c:InputAssociation connector
c21 cso30:c:OutputProcess connector
p9_propro_p9
PMID: 14644140
Based on the results of in vitro
studies using cell lines forcedly expressing SOCS-1, it has
been confirmed that SOCS-1 inhibits various types of
signal transduction through its binding to JAK and
possibly other signaling molecules, such as Vav, IRS-1
sand IL-1 receptor-associated kinase (IRAK)
PMID: 14644140
Currently, SOCS-1 is thought to inhibit the
catalytic activity of JAKs by directly binding to the JAK
activation loop with both its SH2 and KIR domains and
preventing the access of JAK substrates with its KIR
domain.
c22 cso30:c:InputProcess connector
c23 cso30:c:InputProcess connector
c24 cso30:c:OutputProcess connector
p9_propro_p10
PMID: 14644140
Based on the results of in vitro
studies using cell lines forcedly expressing SOCS-1, it has
been confirmed that SOCS-1 inhibits various types of
signal transduction through its binding to JAK and
possibly other signaling molecules, such as Vav, IRS-1
sand IL-1 receptor-associated kinase (IRAK)
c26 cso30:c:InputProcess connector
c25 cso30:c:InputProcess connector
c27 cso30:c:OutputProcess connector
p9_propro_p11
PMID: 14644140
Based on the results of in vitro
studies using cell lines forcedly expressing SOCS-1, it has
been confirmed that SOCS-1 inhibits various types of
signal transduction through its binding to JAK and
possibly other signaling molecules, such as Vav, IRS-1
sand IL-1 receptor-associated kinase (IRAK)
c28 cso30:c:InputProcess connector
c29 cso30:c:InputProcess connector
c30 cso30:c:OutputProcess connector
p9_propro_p12
PMID: 14644140
Based on the results of in vitro
studies using cell lines forcedly expressing SOCS-1, it has
been confirmed that SOCS-1 inhibits various types of
signal transduction through its binding to JAK and
possibly other signaling molecules, such as Vav, IRS-1
sand IL-1 receptor-associated kinase (IRAK)
c31 cso30:c:InputProcess connector
c32 cso30:c:InputProcess connector
c33 cso30:c:OutputProcess connector
p13_propro_p13
PMID: 14644140,12208853,10403376
SOCS-2 is known to bind to the SHP2-binding site of
activated GH receptors and to inhibit the activation
of STAT5b induced by GH
c35 cso30:c:InputProcess connector
c89 cso30:c:InputProcess connector
c34 cso30:c:OutputProcess connector
p15_propro_p15
PMID: 14644140,12208853,10403376
SOCS-2 is known to bind to the SHP2-binding site of
activated GH receptors and to inhibit the activation
of STAT5b induced by GH
c40 cso30:c:InputProcess connector
c41 cso30:c:InputAssociation connector
c42 cso30:c:OutputProcess connector
p16_propro_p16
Growth promotion by GH is
dependent on the induction of insulin-like growth factor-1
(IGF-1) by GH, whereas SOCS-2-deficient mice do not
exhibit an increase in serum IGF-1.
c45 cso30:c:InputAssociation connector
c46 cso30:c:InputAssociation connector
c44 cso30:c:OutputProcess connector
p17_propro_p17
PMID: 14644140,12208853,9727029
SOCS-2 binds not only
to GH receptors but also to IGF-1 receptors
c47 cso30:c:InputProcess connector
c49 cso30:c:InputProcess connector
c43 cso30:c:OutputProcess connector
p18_propro_p18
PMID: 14644140,11331873
In addition, in vitro data have suggested that
SOCS-3 undergoes tyrosine-phosphorylation on stimulation
with IL-2 and appears to accelerate the activation of
ErK (extracellular-signal-regulated kinase) by acting as
an adaptor molecule
c50 cso30:c:InputAssociation connector
c51 cso30:c:InputProcess connector
c52 cso30:c:OutputProcess connector
p19_propro_p19
PMID: 14644140,11331873
In addition, in vitro data have suggested that
SOCS-3 undergoes tyrosine-phosphorylation on stimulation
with IL-2 and appears to accelerate the activation of
ErK (extracellular-signal-regulated kinase) by acting as
an adaptor molecule
c53 cso30:c:InputProcess connector
c55 cso30:c:InputAssociation connector
c54 cso30:c:OutputProcess connector
p20_propro_p20
PMID: 14644140,9889194
SOCS-5 is induced in M1 cell lines in response to stimulation
with IL-6 and marginally inhibits IL-6 signaling
c56 cso30:c:InputAssociation connector
c58 cso30:c:InputAssociation connector
c57 cso30:c:OutputProcess connector
p21_propro_p21
PMID: 14644140,11342531
SOCS-6 binds to insulin receptors and inhibits the
activation of Erk1/2, protein kinase B and IRS-1
c59 cso30:c:InputProcess connector
c48 cso30:c:InputProcess connector
c61 cso30:c:OutputProcess connector
p22_propro_p22
PMID: 14644140,11342531
SOCS-6 binds to insulin receptors and inhibits the
activation of Erk1/2, protein kinase B and IRS-1
c62 cso30:c:InputProcess connector
c78 cso30:c:InputInhibitor connector
c63 cso30:c:OutputProcess connector
p22_propro_p23
PMID: 14644140,11342531
SOCS-6 binds to insulin receptors and inhibits the
activation of Erk1/2, protein kinase B and IRS-1
c66 cso30:c:InputProcess connector
c64 cso30:c:InputInhibitor connector
c67 cso30:c:OutputProcess connector
p22_propro_p24
PMID: 14644140,11342531
SOCS-6 binds to insulin receptors and inhibits the
activation of Erk1/2, protein kinase B and IRS-1
c69 cso30:c:InputProcess connector
c65 cso30:c:InputInhibitor connector
c70 cso30:c:OutputProcess connector
p22_propro_p25
PMID: 14644140,11342531
SOCS-6 binds to insulin receptors and inhibits the
activation of Erk1/2, protein kinase B and IRS-1
c72 cso30:c:InputProcess connector
c68 cso30:c:InputInhibitor connector
c73 cso30:c:OutputProcess connector
p26_propro_p26
PMID: 14644140,12052866
Interestingly, a recent study has reported that SOCS-6
binds to IRS-4, a molecule with an important role in
insulin signaling, and that SOCS-6-deficient mice exhibit
mild growth retardation
c74 cso30:c:InputProcess connector
c75 cso30:c:InputProcess connector
c76 cso30:c:OutputProcess connector
p27_propro_p27
PMID: 14644140,12626585
It is noteworthy that this
notion is in line with the recent finding that SOCS-3
associates with gp130 but not with the IL-10 receptor
(IL-10R), and endogenous SOCS-3 induced by cytokines
inhibits IL-6 signaling but not IL-10 signaling in human
macrophages
PMID: 14644140
SOCS-3 inhibits the function of JAK by binding to the Src homology phosphatase-2 (SHP-2)-binding domain of gp130 and the EPORs
c77 cso30:c:InputProcess connector
c79 cso30:c:OutputProcess connector
c36 cso30:c:OutputProcess connector
p28_propro_p28
PMID: 14644140
SOCS-3 inhibits the function of JAK by binding to the Src homology phosphatase-2 (SHP-2)-binding domain of gp130 and the EPORs
c81 cso30:c:InputProcess connector
c2 cso30:c:InputProcess connector
c82 cso30:c:OutputProcess connector
p29_propro_p29
PMID: 14644140,12754506
Other groups showed that IL-6 strongly activates
STAT1 and induces the expression of IFN-responsive
genes in SOCS-3 deficient macrophages, implying that
IL-6 could mimic the action of IFNs
c83 cso30:c:InputAssociation connector
c84 cso30:c:InputProcess connector
c85 cso30:c:OutputProcess connector
p30_propro_p30
PMID: 14644140,12754506
Other groups showed that IL-6 strongly activates
STAT1 and induces the expression of IFN-responsive
genes in SOCS-3 deficient macrophages, implying that
IL-6 could mimic the action of IFNs
c86 cso30:c:InputAssociation connector
c87 cso30:c:OutputProcess connector
p31_propro_p31
PMID: 14644140,9774439
CIS is also involved in the ubiquitination and degradation of EPO receptors
c60 cso30:c:InputProcess connector
c71 cso30:c:OutputProcess connector
p32_propro_p32
PMID: 14644140,9774439
CIS is also involved in the ubiquitination and degradation of EPO receptors
c90 cso30:c:InputProcess connector
c91 cso30:c:OutputProcess connector
c92 cso30:c:OutputProcess connector
p33_propro_p33
PMID: 14644140,10747851,12228220,11971965
Indeed, SOCS-1 accelerates ubiquitination and degradation of Vav, insulin receptor substrate-1 (IRS-1) and JAKs that can associate with SOCS-1
c98 cso30:c:InputProcess connector
c99 cso30:c:OutputProcess connector
p34_propro_p34
PMID: 14644140,10747851,12228220,11971965
Indeed, SOCS-1 accelerates ubiquitination and degradation of Vav, insulin receptor substrate-1 (IRS-1) and JAKs that can associate with SOCS-1
c93 cso30:c:InputProcess connector
c94 cso30:c:OutputProcess connector
p35_propro_p35
PMID: 14644140,10747851,12228220,11971965
Indeed, SOCS-1 accelerates ubiquitination and degradation of Vav, insulin receptor substrate-1 (IRS-1) and JAKs that can associate with SOCS-1
c95 cso30:c:InputProcess connector
c96 cso30:c:OutputProcess connector
c97 cso30:c:OutputProcess connector
p36_propro_p36
PMID: 14644140,10747851,12228220,11971965
Indeed, SOCS-1 accelerates ubiquitination and degradation of Vav, insulin receptor substrate-1 (IRS-1) and JAKs that can associate with SOCS-1
c100 cso30:c:InputProcess connector
c101 cso30:c:OutputProcess connector
c102 cso30:c:OutputProcess connector
p33_propro_p37
PMID: 14644140,10747851,12228220,11971965
Indeed, SOCS-1 accelerates ubiquitination and degradation of Vav, insulin receptor substrate-1 (IRS-1) and JAKs that can associate with SOCS-1
c103 cso30:c:InputProcess connector
c104 cso30:c:OutputProcess connector
p35_propro_p38
PMID: 14644140,10747851,12228220,11971965
Indeed, SOCS-1 accelerates ubiquitination and degradation of Vav, insulin receptor substrate-1 (IRS-1) and JAKs that can associate with SOCS-1
c105 cso30:c:InputProcess connector
c106 cso30:c:OutputProcess connector
c107 cso30:c:OutputProcess connector
p39_propro_p39
PMID: 14644140,7796808
Initial in vitro studies reported
CIS as an inhibitor of the signal transduction of EPO,
interleukin-2 (IL-2), IL-3, GH and prolactin, by masking
the STAT5-binding sites of receptors and inhibiting
the activation of STAT5.
c108 cso30:c:InputProcess connector
c110 cso30:c:InputInhibitor connector
c109 cso30:c:OutputProcess connector
p39_propro_p40
PMID: 14644140,7796808
Initial in vitro studies reported
CIS as an inhibitor of the signal transduction of EPO,
interleukin-2 (IL-2), IL-3, GH and prolactin, by masking
the STAT5-binding sites of receptors and inhibiting
the activation of STAT5.
c111 cso30:c:InputInhibitor connector
c112 cso30:c:InputProcess connector
c113 cso30:c:OutputProcess connector
p39_propro_p41
PMID: 14644140,7796808
Initial in vitro studies reported
CIS as an inhibitor of the signal transduction of EPO,
interleukin-2 (IL-2), IL-3, GH and prolactin, by masking
the STAT5-binding sites of receptors and inhibiting
the activation of STAT5.
c114 cso30:c:InputInhibitor connector
c115 cso30:c:InputProcess connector
c116 cso30:c:OutputProcess connector
p39_propro_p42
PMID: 14644140,7796808
Initial in vitro studies reported
CIS as an inhibitor of the signal transduction of EPO,
interleukin-2 (IL-2), IL-3, GH and prolactin, by masking
the STAT5-binding sites of receptors and inhibiting
the activation of STAT5.
c117 cso30:c:InputInhibitor connector
c118 cso30:c:InputProcess connector
c119 cso30:c:OutputProcess connector
p39_propro_p43
PMID: 14644140,7796808
Initial in vitro studies reported
CIS as an inhibitor of the signal transduction of EPO,
interleukin-2 (IL-2), IL-3, GH and prolactin, by masking
the STAT5-binding sites of receptors and inhibiting
the activation of STAT5.
c120 cso30:c:InputProcess connector
c122 cso30:c:InputInhibitor connector
c121 cso30:c:OutputProcess connector
p14_propro_p14
PMID: 14644140,12208853,10403376
SOCS-2 is known to bind to the SHP2-binding site of
activated GH receptors and to inhibit the activation
of STAT5b induced by GH
c37 cso30:c:InputProcess connector
c38 cso30:c:InputProcess connector
c39 cso30:c:OutputProcess connector
CIS_enti_MO000017116
CIS
Ligand:EpoR_enti_e5
Ligand:EpoR
GHR_enti_MO000017329
GHR
IL-2:IL-2R_enti_e11
IL-2:IL-2R
IL-3:IL-3R_enti_e12
IL-3:IL-3R
Ligand:Prolactin_enti_e14
Ligand:Prolactin
insulin_enti_MO000007556
insulin
SOCS1_enti_G010539
SOCS1
LPS_enti_MO000016882
LPS
CpGDNA_enti_e15
CpGDNA
SOCS-1_enti_MO000017004
SOCS-1
JAK_enti_e16
JAK
SOCS-1:JAK_enti_e17
SOCS-1:JAK
Vav_enti_MO000000044
Vav
SOCS-1:Vav_enti_e18
SOCS-1:Vav
IRS-1_enti_MO000000154
IRS-1
SOCS-1:IRS-1_enti_e19
SOCS-1:IRS-1
IRAK_enti_MO000000213
IRAK
SOCS-1:iRAK_enti_e20
SOCS-1:iRAK
SOCS-2_enti_MO000017120
SOCS-2
STAT5B_enti_MO000013133
STAT5B
GH_enti_MO000017890
GH
GH:GHR_enti_e22
GH:GHR
STAT5B{active}_enti_e23
STAT5B{active}
IGF-1_enti_MO000017094
IGF-1
IGF1_enti_G014721
IGF1
IGF-1:IGF-1R_enti_e24
IGF-1:IGF-1R
SOCS-3_enti_MO000017121
SOCS-3
IL-2_enti_MO000017061
IL-2
SOCS-3{p}_enti_e25
SOCS-3{p}
ERK_enti_MO000000011
ERK
ERK{active}_enti_e26
ERK{active}
SOCS-5_enti_MO000035128
SOCS-5
IL-6_enti_MO000007384
IL-6
SOCS5_enti_G012007
SOCS5
SOCS6_enti_MO000062651
SOCS6
Insulin:Insulin receptor_enti_e28
Insulin:Insulin receptor
ERK1_enti_MO000004670
ERK1
ERK1{active}_enti_e29
ERK1{active}
ERK2_enti_MO000004676
ERK2
ERK2{active}_enti_e30
ERK2{active}
protein kinase B_enti_e31
protein kinase B
protein kinase B {active}_enti_e32
protein kinase B {active}
IRS-1{active}_enti_e33
IRS-1{active}
IRS-4_enti_MO000016866
IRS-4
SOCS6:IRS-4_enti_e34
SOCS6:IRS-4
Ligand:gp130_enti_e35
Ligand:gp130
STAT1_enti_MO000013119
STAT1
STAT1{active}_enti_e37
STAT1{active}
IFN responsive genes_enti_e38
IFN responsive genes
Ligand:Prolactin:CIS_enti_e39
Ligand:Prolactin:CIS
GH:GHR:CIS_enti_e6
GH:GHR:CIS
LIgand:EpoR:CIS_enti_e13
LIgand:EpoR:CIS
Ligand:EpoR:SOCS-3_enti_e40
Ligand:EpoR:SOCS-3
IL-2:IL-2R:CIS_enti_e36
IL-2:IL-2R:CIS
IL-3:IL-3R:CIS_enti_e41
IL-3:IL-3R:CIS
GH:GHR:SOCS-2_enti_e21
GH:GHR:SOCS-2
Ligand:gp130:SOCS-3_enti_e42
Ligand:gp130:SOCS-3
IGF-1:IGF-1R:SOCS-2_enti_e43
IGF-1:IGF-1R:SOCS-2
Insulin:Insulin receptor:SOCS6_enti_e44
Insulin:Insulin receptor:SOCS6
LIgand:EpoR{ub}:CIS_enti_e27
LIgand:EpoR{ub}:CIS
Ligand_enti_e45
Ligand
SOCS-1:Vav{ub}_enti_e46
SOCS-1:Vav{ub}
degradants_enti_e47
SOCS-1:IRS-1{ub}_enti_e48
SOCS-1:IRS-1{ub}
SOCS-1:JAK{ub}_enti_e49
SOCS-1:JAK{ub}
STAT5_enti_MO000016876
STAT5
STAT5{active}_enti_e63
STAT5{active}