◀ Back to IGF1
IGF1 — IRS2
Pathways - manually collected, often from reviews:
-
NCI Pathway Database IGF1 pathway:
IRS2/Crk complex (IRS2-CRK)
→
IGF-1R heterotetramer/IGF1/IRS1 complex (IGF1R-IGF1-IRS1)
(modification, collaborate)
Beitner-Johnson et al., J Biol Chem 1996
Evidence: mutant phenotype, assay
-
Reactome Reaction:
IGF1
→
IRS2
(indirect_complex)
Karas et al., Endocrinology 2001, Schreyer et al., Endocrinology 2003, Kim et al., Oncogene 2004, Rakatzi et al., Arch Physiol Biochem 2006, Cuevas et al., J Hepatol 2007, Siemeister et al., J Biol Chem 1995, Xu et al., J Biol Chem 1995, He et al., J Biol Chem 1996*, Takahashi et al., Endocrinology 1997, Fantin et al., J Biol Chem 1998, Kim et al., Endocrinology 1998, Kim et al., J Biol Chem 1998
-
Reactome Reaction:
IGF1
→
IRS2
(reaction)
Karas et al., Endocrinology 2001, Schreyer et al., Endocrinology 2003, Kim et al., Oncogene 2004, Rakatzi et al., Arch Physiol Biochem 2006, Cuevas et al., J Hepatol 2007, Siemeister et al., J Biol Chem 1995, Xu et al., J Biol Chem 1995, He et al., J Biol Chem 1996*, Takahashi et al., Endocrinology 1997, Fantin et al., J Biol Chem 1998, Kim et al., Endocrinology 1998, Kim et al., J Biol Chem 1998
Text-mined interactions from Literome
Venters et al., Proc Natl Acad Sci U S A 1999
(Nerve Degeneration) :
TNF-alpha suppresses
IGF-I induced tyrosine phosphorylation of
insulin receptor substrate 2 (IRS-2) and inhibits IRS-2-precipitable phosphatidylinositol 3'-kinase activity
Auclair et al., J Clin Endocrinol Metab 1999
(Insulin Resistance) :
In contrast, cell resistance to IGF-I occurred at a step distal to IGF-I receptors (IGF-IRs), as AIRs altered neither IGF-I binding nor IGF-I induced IGF-IR autophosphorylation, but inhibited the ability of IGF-IRs to mediate tyrosine phosphorylation of IRS-1 and
IRS-2 in
response to
IGF-I
Ariga et al., Biochem J 2000
:
In contrast, cAMP pretreatment potentiated the tyrosine phosphorylation of
IRS-2 induced by
IGF-I , but did not affect the amount of IRS-2
Richards et al., Endocrinology 2001
:
Collectively, these data suggest that the E2-induced decrease in uterine
insulin receptor substrate-2 requires
IGF-I signaling, is not dependent solely on insulin receptor substrate-1 and PI3K, and is blocked by progesterone as well as by pharmacological inhibition of proteasomal protease activity
Rui et al., J Biol Chem 2001
(Carcinoma, Hepatocellular...) :
Regulation of
insulin/insulin-like growth factor-1 signaling by proteasome mediated degradation of
insulin receptor substrate-2 ... In this study, we show that insulin,
IGF-1 , or osmotic stress
promoted ubiquitin/proteasome mediated degradation of
IRS-2 in 3T3-L1 cells, Fao hepatoma, cells and mouse embryo fibroblasts ; however, insulin/IGF-1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts ... In this study, we show that insulin,
IGF-1 , or osmotic stress
promoted ubiquitin/proteasome mediated degradation of
IRS-2 in 3T3-L1 cells, Fao hepatoma, cells and mouse embryo fibroblasts ; however, insulin/IGF-1 did not promote degradation of IRS-1 in 3T3-L1 preadipocytes or mouse embryo fibroblasts ... MG132 or lactacystin, specific inhibitors of 26S proteasome, blocked
insulin/IGF-1 induced degradation of
IRS-2 and enhanced the detection of ubiquitinated IRS-2
Lingohr et al., Diabetes 2002
(MAP Kinase Signaling System) :
It was found that
IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate
(IRS)-1 and -2 in a glucose dependent manner, whereas TGF-alpha/EGF did not
Wrede et al., J Mol Endocrinol 2003
:
PMA inhibited IGF-I induced activation of PKB, correlating with inhibition of
IGF-I induced association of
IRS-2 with the p85 regulatory subunit of phosphatidylinositol-3 kinase
Morelli et al., Oncogene 2003
(Breast Neoplasms) :
The stabilization of IRS-1 in MDA-MB-231/ER cells was paralleled by the upregulation of the IRS-1/Akt/GSK-3 pathway and improved survival in the presence of IGF-I, whereas
IRS-2 was not
involved in
IGF-I signaling
Lingohr et al., Mol Cell Endocrinol 2003
:
However, increased IRS-3 expression blocked
glucose/IGF-1 induced
IRS-2 translocation from the cytosol to the plasma membrane, dampening IRS-2/IGF-1R interaction and subsequent activation of the PI3K/PKB/GSK3 signaling pathway
Zhang et al., Breast Cancer Res Treat 2004
(Breast Neoplasms) :
Immunoprecipitation of IRS substrates followed by anti-phosphotyrosine blotting demonstrated that both IRS-1 and
IRS-2 were
activated by
IGF-I in these cells
Xin et al., Am J Physiol Gastrointest Liver Physiol 2004
(Crohn Disease) :
Immunoprecipitation studies demonstrated that
IGF-I stimulation
resulted in tyrosine phosphorylation of IRS-1,
IRS-2 , and Shc
Vincent et al., Neurobiol Dis 2004
:
IGF-I :
IGF-IR signaling
involves phosphorylation of IRS-1 and Shc, but not
IRS-2
Briaud et al., J Biol Chem 2005
(Diabetes Mellitus, Type 2) :
This
glucose/IGF-1 induced decrease in
IRS-2 levels was prevented by the proteasomal inhibitor, lactacystin ... In addition, the
glucose/IGF-1 induced increase in Ser/Thr phosphorylation of IRS-2 and the subsequent decrease in INS-1 cell
IRS-2 protein levels was thwarted by the mammalian target of rapamycin ( mTOR ) inhibitor, rapamycin ... Moreover, adenoviral mediated expression of constitutively active mTOR ( mTORDelta ) further increased
glucose/IGF-1 induced Ser/Thr phosphorylation of
IRS-2 and decreased IRS-2 protein levels, whereas adenoviral mediated expression of `` kinase-dead '' mTOR ( mTOR-KD ) conversely reduced Ser/Thr phosphorylation of IRS-2 and maintained IRS-2 protein levels
Kim et al., Endocrinology 2005
(Neuroblastoma) :
Insulin-like growth factor I induces preferential degradation of
insulin receptor substrate-2 through the phosphatidylinositol 3-kinase pathway in human neuroblastoma cells ... In summary, 1 )
IRS-2 is more sensitive to IGF-I mediated degradation ; 2 ) IRS degradation is mediated by phosphatidylinositol 3-kinase and proteasome sensitive pathways ; and 3 ) high levels of
IGF-IR , and possibly the subsequent increase in Akt phosphorylation, are
required for efficient IRS degradation
Denley et al., Mol Cell Biol 2007
:
The specific
activation of
IRS-2 by
IGF-I through the IR does not result in activation of the extracellular signal regulated kinase pathway but does induce delayed low-level activation of the phosphatidylinositol 3-kinase pathway and biological effects such as enhanced cell viability and protection from apoptosis
Barnes et al., Clin Cancer Res 2007
(Head and Neck Neoplasms) :
Pretreatment of serum starved 183A or TU159 SCCHN cell lines with A12 ( 10 microg/mL ) blocked
IGF stimulated activation of IGF-IR, insulin receptor substrate (IRS)-1 and
IRS-2 , mitogen activated protein kinase, and phosphatidylinositol 3-kinase
Heckman et al., Dev Biol 2007
:
Because both
IGF and p190-B signaling
affect IRS-1/2 , we examined IRS-1/2 double knockout embryonic mammary buds
Simmons et al., Am J Physiol Gastrointest Liver Physiol 2007
:
In contrast,
IGF-I activated both IRS-1 and
IRS-2 in intestinal myofibroblasts and IRS-2 activation was upregulated in IRS-1-null myofibroblasts ... In contrast,
IGF-I activated both IRS-1 and
IRS-2 in intestinal myofibroblasts and IRS-2 activation was upregulated in IRS-1-null myofibroblasts
Hers et al., Blood 2007
:
IGF-1 stimulated tyrosine phosphorylation of IRS-1 and
IRS-2 and subsequent p85 binding is transient and precedes phosphorylation of protein kinase B (PKB) on Ser473
Nemoto et al., J Pharmacol Sci 2009
:
In cultured bovine adrenal chromaffin cells, 1 ) constitutive and negatively regulated activities of GSK-3beta up- and down-regulated insulin receptor, insulin receptor substrate-1 (IRS-1), IRS-2, and Akt levels via controlling proteasomal degradation and protein synthesis ; 2 ) nicotinic receptor/protein kinase C-alpha (PKC-alpha)/extracellular signal regulated kinase ( ERK ) pathway
up-regulated IRS-1 and
IRS-2 levels, enhancing insulin induced the phosphoinositide 3-kinase (PI3K)/Akt/GSK-3beta pathway ; 3 ) inhibition of calcineurin by cyclosporin A or FK506 down-regulated IRS-2 level, attenuating insulin-like growth factor-I (IGF-I) induced ERK and GSK-3beta pathways ; and 4 ) insulin,
IGF-I or therapeutics ( e.g., lithium ) up-regulated the voltage dependent Na(v)1.7 sodium channel
Kwon et al., Cancer Res 2009
(Adenocarcinoma...) :
Furthermore, we also showed that insulin receptor substrate
(IRS)-2 , but not IRS-1, is
involved in regulation of
IGF-IR expression, which is most likely not transcriptional control ... Overall, these findings suggest a novel regulatory
role of
IRS-2 on the expression of
IGF-IR through PKCdelta and mTOR in pancreatic cancer cells
de Blaquière et al., Endocr Relat Cancer 2009
(Breast Neoplasms) :
We conclude that both IRS-1 and
IRS-2 control the migratory response of breast cancer cells to
IGF-1 and may, therefore, be key molecules in determining breast cancer spread
Kwon et al., Nutrition 2011
:
This improvement was associated with
insulin/insulin-like growth factor-1 signaling that was
activated by the tyrosine phosphorylation of
insulin receptor substrate-2 and serine phosphorylation of Akt, and this in turn increased pancreatic and duodenal homeobox-1 expression
Sadagurski et al., Cell Metab 2012
(Glucose Intolerance...) :
Irs2 mediated
insulin/IGF1 signaling in the CNS modulates energy balance and glucose homeostasis ; however, the site for Irs2 function is unknown
Fukushima et al., J Biol Chem 2012
:
In these cells,
IGF-I stimulation
induced tyrosine phosphorylation of IGF-IR and
IRS-1/2 , but mutated IGF-IR failed to bind PI3K and to induce maximal phosphorylation of GSK3ß and cell proliferation in response to IGF-I
Neukamm et al., PloS one 2012
:
IGF-1 stimulation
led to increased binding of 14-3-3 to
IRS-2 in transfected HEK293 cells and this binding was prevented by inhibition of the PI 3-kinase pathway and an Akt/PKB inhibitor
Haddad et al., J Biol Chem 1997
:
Pretreatment of bovine fibroblasts with 10 nM insulin for 48 h blocked subsequent
IGF-I stimulated DNA synthesis and the IGF-I induced increase in tyrosyl phosphorylated
IRS-2 ... Nonetheless, pretreatment of bovine fibroblasts with IL-4 inhibited IGF-I stimulated DNA synthesis by 50-60 %, concomitant with a decrease in
IGF-I induced
IRS-2 phosphorylation
Valverde et al., Mol Endocrinol 1998
:
Insulin/IGF-I rapidly
stimulated IRS-1 and
IRS-2 tyrosine phosphorylation, their association with p85alpha, and IRS-1- and IRS-2 associated phosphatidylinositol (PI) 3-kinase activation to the same extent, the effect of insulin being stronger than the effect of IGF-I at the same physiological dose ( 10 nM ) ... Pull-down experiments with glutathione-S-transferase-fusion proteins containing SH2-domains of p85alpha revealed a strong association between IRS-1 and
IRS-2 with p85alpha in
response to
insulin/IGF-I , the insulin effect being stronger than IGF-I
Dews et al., Recept Signal Transduct 1997
:
Although the mitogenic function of the
IGF-IR may
require the activation of insulin receptor substrate-1 (IRS-1) or
IRS-2 , an overexpressed IGF-IR is able to protect 32D cells, which lack IRS-1 and IRS-2, from apoptosis caused by Interleukin-3 (IL-3) withdrawal
Kornmann et al., Cancer Res 1998
(Colonic Neoplasms...) :
Insulin,
IGF-I , and IGF-II enhanced the growth of both cell lines,
stimulated tyrosine phosphorylation of
IRS-2 , and increased IRS-2 associated phosphatidylinositol (PI) 3-kinase activity
Kim et al., Endocrinology 1998
(Neuroblastoma) :
We report here that
IGF-I stimulated the tyrosine phosphorylation of the type I IGF receptor ( IGF-IR ) and
insulin receptor substrate-2 (IRS-2) in a time- and concentration dependent manner ... Treatment of the cells with PI 3-K inhibitors ( wortmannin and LY294002 ) increased
IGF-I induced tyrosine phosphorylation of
IRS-2
Horney et al., Am J Physiol 1998
(Diabetic Nephropathies) :
MMCs in HG displayed increased
IGF-I stimulated
insulin receptor substrate-1/2 phosphorylation and activator protein-1 transcriptional activity compared with NG controls
Kim et al., J Biol Chem 1998
(Neuroblastoma) :
Insulin receptor substrate 2 and Shc
play different roles in
insulin-like growth factor I signaling ... In contrast,
IGF-I induces a transient tyrosine phosphorylation of IRS-2 and an association of
IRS-2 with Grb2 ... In contrast,
IGF-I induces a transient tyrosine phosphorylation of IRS-2 and an association of
IRS-2 with Grb2