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AKT1 — IRS1

Pathways - manually collected, often from reviews:

• OpenBEL Selventa BEL large corpus: AKT1 → IRS1 (increases)
  Evidence: IRS-1 knockdown in both cell lines resulted in reduction of insulin stimulated Akt1 phosphorylation at Ser 473. In parental HepG2 cells, IRS-1 knockdown resulted in reduction (ca. 50%) in the basal level of phosphorylated mTOR (Ser 2448) irrespective of insulin treatment.
• WikiPathways Insulin Signaling: Complex of IRS1-PIK3CA → GSK3B/AKT2/AKT1/SGK3/SGK1/GSK3A/PDPK1/SGK2 (activation)
  

Protein-Protein interactions - manually collected from original source literature:

Studies that report less than 10 interactions are marked with *

• IRef Biogrid Interaction: AKT1 — IRS1 (physical association, affinity chromatography technology) Paz et al., J Biol Chem 1999*
• IRef Hprd Interaction: AKT1 — IRS1 (in vivo) Paz et al., J Biol Chem 1999*
• IRef Ophid Interaction: AKT1 — IRS1 (aggregation, interologs mapping) Brown et al., Bioinformatics 2005

Text-mined interactions from Literome

Ueki et al., J Clin Invest 2000 (Insulin Resistance) : In primary hepatocytes isolated from null mice, expression of IRS-1 enhanced both PI3K and PKB activities, but expression of IRS-1Deltap85 enhanced only PKB
Carvalho et al., Mol Cell Biochem 2000 (Insulin Resistance...) : There was a marked impairment in the insulin stimulated tyrosine phosphorylation of IRS-1 and 2 as well as activation of PI3-kinase and PKB in cells from old and obese animals
Ozes et al., Proc Natl Acad Sci U S A 2001 (Insulin Resistance) : Conversely, TNF inhibition of IRS-1 tyrosine phosphorylation was blocked by kinase dead Akt
Telting et al., Arch Physiol Biochem 2001 : EIR-Y1158F was impaired in its ability to phosphorylate insulin receptor substrate (IRS)-1 and induce downstream signals of IRS-1 phosphorylation, such as the association of IRS-1 with phosphatidyl-inositol-3'-kinase and the activation of protein kinase B ( Akt )
Sadowski et al., Endocrinology 2001 : We therefore tested the C2C12 myogenic cell line for its response to GH and demonstrate that C2C12 skeletal muscle cells rapidly respond to physiological levels of GH with increased tyrosine phosphorylation of the GH receptor, Janus kinase 2, signal transducer and activator of transcription-5a and -5b, insulin receptor substrate-1 , and activation of MAPKs/ERKs and protein kinase B/Akt ... We therefore tested the C2C12 myogenic cell line for its response to GH and demonstrate that C2C12 skeletal muscle cells rapidly respond to physiological levels of GH with increased tyrosine phosphorylation of the GH receptor, Janus kinase 2, signal transducer and activator of transcription-5a and -5b, insulin receptor substrate-1 , and activation of MAPKs/ERKs and protein kinase B/Akt
Rui et al., J Biol Chem 2001 (Carcinoma, Hepatocellular...) : By contrast, IRS-1 activation of Akt and ERK1/2 was not inhibited by chronic insulin/IGF-1 stimulation in IRS-2-deficient mouse embryo fibroblasts
Goetze et al., Biochem Biophys Res Commun 2001 : Thus, TNFalpha selectively interferes with insulin 's antiapoptotic signaling in VSMC by inhibiting the association of IRS-1/PI3K and the downstream activation of Akt
Laviola et al., Diabetes 2001 (Diabetes Mellitus, Experimental) : In conclusion, in the diabetic heart, 1 ) IRS-1 , IRS-2, and p52 ( Shc ) are differently altered, 2 ) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated , and 3 ) the increased activity of proximal signaling proteins ( i.e., IRS-2 and PI 3-kinase ) is not propagated distally to GSK-3
Standaert et al., Endocrinology 2002 : Presently, in 3T3/L1 adipocytes, rosiglitazone induced sizable increases in basal glucose transport that were : dependent on PI3K, 3-phosphoinositide dependent protein kinase-1 ( PDK-1 ), and PKC-lambda ; accompanied by increases in tyrosine phosphorylation of Cbl and Cbl dependent increases in PI3K and PKC-lambda activity ; but not accompanied by increases in IRS-1/2 dependent PI3K or protein kinase B activity
Garrouste et al., Cell Death Differ 2002 : In this model, IGF-I did not activate the focal adhesion kinase, whereas it induced tyrosine phosphorylation of the insulin receptor substrate-1 and activation of the extracellular signal related kinase 1 and 2, p38, phosphatidylinositol 3'-kinase and protein kinase B/Akt ... In this model, IGF-I did not activate the focal adhesion kinase, whereas it induced tyrosine phosphorylation of the insulin receptor substrate-1 and activation of the extracellular signal related kinase 1 and 2, p38, phosphatidylinositol 3'-kinase and protein kinase B/Akt
Jost et al., Am J Physiol Endocrinol Metab 2002 (Insulin Resistance) : Stimulation with CGP-12177 did not impair insulin receptor kinase activity but decreased insulin receptor substrate-1 binding to phosphatidylinositol (PI) 3-kinase and activation of protein kinase B
Dietze et al., Diabetes 2002 : Addition of tumor necrosis factor (TNF)-alpha ( 2.5 nmol/l ) to myocytes for 48 h reduced IRS-1 expression and inhibited IRS-1 and Akt phosphorylation comparable to the effect of co-culture
Lima et al., Endocrine 2002 (Diabetes Mellitus, Experimental...) : In the present study, we investigated insulin induced IRS-1/SHP2 and IRS-1/PI 3-kinase associations and the regulation of a downstream serine-kinase AKT/PKB in liver and muscle of three animal models of insulin resistance : STZ diabetes, epinephrine treated rats, and aging, which have alterations in IRS-1 tyrosine phosphorylation in common
Sedaghat et al., Am J Physiol Endocrinol Metab 2002 (Insulin Resistance) : A novel mechanistic model of postreceptor events including phosphorylation of insulin receptor substrate-1 , activation of phosphatidylinositol 3-kinase, and subsequent activation of downstream kinases Akt and protein kinase C-zeta is coupled with previously validated subsystem models of insulin receptor binding, receptor recycling, and GLUT4 translocation
Kaburagi et al., Biochem Biophys Res Commun 2003 : Overexpressed IRS-3 as well as IRS-1 enhanced phosphoinositide (PI) 3-kinase activity in response to insulin and increased phosphorylation of protein kinase B (PKB) at S473 and phosphorylation of one of the members of the forkhead transcription factor FKHRL1 on T32 in both insulin untreated and -treated states
Murata et al., J Biol Chem 2003 : The following cellular processes were observed in vitro in a manner dependent on insulin, time of incubation, and exogenous ATP : 1 ) autophosphorylation and activation of the insulin receptor ; 2 ) tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) ; 3 ) association of tyrosine phosphorylated IRS-1 with phosphoinositide 3-kinase ; 4 ) activation of the kinase Akt via its phosphorylation on Thr-308 and Ser-473 ; and 5 ) phosphorylation of glycogen synthase kinase-3 by activated Akt ... Additionally, data are provided demonstrating that full Akt activation in this system is dependent on plasma membrane associated IRS-1 , can not be mediated by robust cytosol-specific tyrosine phosphorylation of IRS-1, and occurs in the complete absence of detectable IRS-2 phosphorylation in the cytosol and plasma membrane
Cooney et al., EMBO J 2004 : In the liver, despite lower IR autophosphorylation, enhanced insulin induced tyrosine phosphorylation of insulin receptor substrate (IRS)-1 and activation of protein kinase B (PKB) was observed
Sajan et al., Mol Endocrinol 2004 : However, it is uncertain whether aPKC and PKB are activated together or differentially in response to IRS-1 and IRS-2 activation in insulin-sensitive tissues ... These results suggest that IRS-1 is required for : 1 ) activation of both aPKC and PKB in muscle ; 2 ) aPKC, but not PKB, activation in adipocytes ; and 3 ) PKB, but not aPKC, activation in liver
Duan et al., J Biol Chem 2004 : Consequently, SH2-B dramatically enhanced leptin stimulated tyrosine phosphorylation of IRS1 and IRS2 in HEK293 cells stably expressing LRb, thus promoting association of IRS1 and IRS2 with the p85 regulatory subunit of PI 3-kinase and phosphorylation and activation of Akt
Nagasawa et al., Biochem J 2005 : EP2 stimulation failed to inhibit tyrosine phosphorylation either of IGF-I receptor or IRS-1 ( insulin receptor substrate-1 ), or activation of phosphoinositide 3-kinase or Akt in response to IGF-I, but potently and dose-dependently inhibited IGF-I induced activation of cellular Rac activity and membrane ruffling
Khamzina et al., Endocrinology 2005 (Disease Models, Animal...) : Time-course studies also revealed that mTOR and S6K1 activation by insulin was accelerated in tissues of obese rats, in association with increased inhibitory phosphorylation of insulin receptor substrate-1 (IRS-1) on Ser636/Ser639 and impaired Akt activation
Gual et al., Biochimie 2005 (Insulin Resistance) : The activation of PKB in response to insulin propagates insulin signaling and promotes the phosphorylation of IRS1 on serine residue in turn generating a positive-feedback loop for insulin action
Eyster et al., J Biol Chem 2005 : We found that latrunculin treatment did not affect insulin dependent tyrosine phosphorylation of the insulin receptor beta-subunit and IRS-1 but completely inhibited activation of Akt/PKB enzymatic activity ... We found that latrunculin treatment did not affect insulin dependent tyrosine phosphorylation of the insulin receptor beta-subunit and IRS-1 but completely inhibited activation of Akt/PKB enzymatic activity
Huang et al., J Biol Chem 2005 : We conclude that insulin stimulated Akt1 phosphorylation, actin remodeling, GLUT4 translocation, and glucose uptake are regulated mainly by IRS-1 , whereas IRS-2 contributes selectively to ERK signaling, and Akt2 and p38MAPK lie downstream of both IRS in muscle cells
Bridgewater et al., Kidney Int 2005 : IGF-1 stimulation resulted in the formation of the insulin receptor substrate (IRS)-1-p85 complex, an increase in PI3 kinase activity, and activation of protein kinase B ( AKT/PKB ) and the bcl-2 family member bad
Taniyama et al., Arterioscler Thromb Vasc Biol 2005 : Recently, serine phosphorylation and degradation of insulin receptor substrate-1 (IRS-1) were shown to inhibit Akt activation and reduce glucose uptake
Rajala et al., Biochemistry 2005 : We suggest that the Grb14 NPXY motif could be acting as a dominant negative for IRS-1 functions in the retina, and this hypothesis is consistent with the recent study that Grb14-deficient mice exhibit enhanced IRS-1 phosphorylation and activation of protein kinase B
Asano et al., Cancer Res 2005 (Pancreatic Neoplasms) : Furthermore, IRS-1 was phosphorylated on a p85 binding site ( Y ( 612 ) ), and IRS-specific small interfering RNA potently inhibited activation of PI3K and Akt in transfected cells
Tzatsos et al., Mol Cell Biol 2006 (Diabetes Mellitus, Type 2) : Thus, diabetes related hyperglycemia hyperactivates the mTOR pathway and may lead to insulin resistance due to suppression of IRS-1 dependent PI3-kinase/Akt signaling
Luna et al., Diabetologia 2006 (Diabetes Mellitus, Type 2) : In contrast, IRS-1 dependent phosphatidylinositol (PI) 3-kinase activity and Ser473 phosphorylation of protein kinase B were not altered by metformin therapy, whereas the responsiveness of muscle aPKC to PI-3,4,5- ( PO ( 4 ) ) ( 3 ), the lipid product of PI 3-kinase, was improved
Sutton et al., Endocrinology 2006 (Insulin Resistance...) : Insulin resistance, assessed by insulin and glucose tolerance tests, Ser ( 307 ) phosphorylation of insulin receptor substrate 1 , and activation of protein kinase B , was examined in control and DIO wild-type ( WT ), Mc3rKO and Mc4rKO C57BL/6J mice
Su et al., J Biol Chem 2006 : Insulin stimulated Interaction between insulin receptor substrate 1 and p85alpha and activation of protein kinase B/Akt require Rab5 ... Insulin stimulated Interaction between insulin receptor substrate 1 and p85alpha and activation of protein kinase B/Akt require Rab5
Wei et al., J Biol Chem 2006 : Furthermore, Ang II abolished insulin induced tyrosine phosphorylation of insulin receptor substrate 1 (IRS1) , activation of protein kinase B ( Akt ), and glucose transporter-4 (GLUT4) translocation to the plasma membrane, which was reversed by pretreating myotubes with losartan or apocynin
Zecchin et al., Diabetes 2007 (Obesity) : In addition, ACh induces JAK2/IRS-1 and IRS-1/phosphatidylinositol (PI) 3-kinase associations, downstream activation of Akt/protein kinase B, endothelial cell-nitric oxide synthase ( eNOS ), and extracellular signal regulated kinase ( ERK ) -1/2
Tzatsos et al., J Biol Chem 2007 : Phosphorylation of IRS-1 at this site inhibited phosphatidylinositol 3-kinase/Akt signaling, suppressed the mitochondrial membrane potential, and promoted apoptosis
Fulzele et al., J Biol Chem 2007 : In DeltaIGF-1R osteoblasts, insulin signaling was markedly increased as evidenced by increased phosphorylation of insulin receptor substrate 1/2 and enhanced ERK/Akt activation
Luo et al., Endocrinology 2007 : These results suggest that a feed-forward mechanism may exist whereby insulin activation of Akt leads to phosphorylation of IRS-1 at Ser ( 629 ), resulting in decreased phosphorylation of IRS-1 at Ser ( 636 ) and enhanced downstream signaling
Hadsell et al., J Endocrinol 2007 (Weight Loss) : The loss of IRS-1 was associated with a compensatory increase in insulin induced IRS-2 phosphorylation ; however, the loss of IRS-1 did also cause a reduction in insulin dependent mammary gland-specific activation of Akt phosphorylation
MacAulay et al., Cell Metab 2007 : Insulin stimulated protein kinase B ( PKB/Akt ) and GSK-3beta phosphorylation was higher in GSK-3alpha KO livers compared to wild-type littermates, and IRS-1 expression was markedly increased
Li et al., Diabetes 2008 (Hyperhomocysteinemia) : Hcy impaired glucose transport and, particularly, the insulin signaling pathway as shown by decreased insulin stimulated tyrosine phosphorylation of insulin receptor and insulin receptor substrate (IRS)-1, increased serine phosphorylation of IRS-1 , and inhibited Akt phosphorylation both in vitro and in vivo, and these impairments were accompanied by an increase in resistin expression
Beeson et al., Metab Syndr Relat Disord 2004 : In obese subjects and obese subjects who had evidence of the polycystic ovary syndrome, insulin stimulated glucose disposal and atypical protein kinase C activation were diminished, whereas activation of insulin receptor substrate-1 dependent phosphatidylinositol 3-kinase and protein kinase B trended lower, but not significantly
Cursio et al., Langenbecks Arch Surg 2009 (Reperfusion Injury) : Shc tyrosine phosphorylation and activation of ERK1/2 were increased after reperfusion, while tyrosine phosphorylation of IRS-1 and activation of PKB/Akt were decreased ... Shc tyrosine phosphorylation and activation of ERK1/2 were increased after reperfusion, while tyrosine phosphorylation of IRS-1 and activation of PKB/Akt were decreased
Temofonte et al., Diabetologia 2009 (Diabetes Mellitus) : Combined thiazolidinedione-metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1 dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle ... Combined thiazolidinedione-metformin treatment synergistically improves insulin signalling to insulin receptor substrate-1 dependent phosphatidylinositol 3-kinase, atypical protein kinase C and protein kinase B/Akt in human diabetic muscle
Shimwell et al., Oncogene 2009 (Cell Transformation, Viral) : However, Ad5E1A associates with IRS-1 , increasing Akt and GSK-3beta phosphorylation and tyrosine phosphorylation of IRS-1 itself
Sajan et al., J Lipid Res 2009 (Disease Models, Animal...) : Moreover, in high-fat fed mice, impaired insulin signaling to IRS-1 dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed ... Moreover, in high-fat fed mice, impaired insulin signaling to IRS-1 dependent phosphatidylinositol 3-kinase, PKB/Akt and aPKC in muscle and hyperinsulinemia were largely reversed
Tzatsos et al., J Biol Chem 2009 : However, under diabetic mimicking conditions mTOR inhibits phosphatidylinositol (PI) 3-kinase/Akt signaling by phosphorylating insulin receptor substrate-1 (IRS-1) at Ser-636/639
Gogg et al., Diabetes 2009 (Diabetes Mellitus, Type 2) : The IRS-1 protein expression was reduced and the serine phosphorylation of PKB in response to insulin attenuated whereas basal and insulin stimulated phosphorylation of extracellular signal related kinase ( ERK ) 1/2 was increased in type 2 diabetes MVEC
Treebak et al., Am J Physiol Cell Physiol 2009 : In soleus from 129S6/sv mice, insulin receptor substrate 1-associated phosphatidylinositol 3 (PI3)-kinase activity was markedly increased with A-769662, and Akt phosphorylation and glucose uptake were inhibited by wortmannin while phosphorylation of acetyl-CoA carboxylase ( S227 ) was unaffected
Yin et al., J Biol Chem 2009 : In normal human chondrocytes, tBHP triggered strong IRS-1 ( Ser-312 and Ser-616 ) and ERK phosphorylation and inhibited IGF-I induced IRS-1 ( Tyr-612 ) and Akt phosphorylation
Arellano-Plancarte et al., Biochem Pharmacol 2010 (Insulin Resistance) : To investigate the potential interactions between the angiotensin II (Ang II) and insulin signaling systems, regulation of IRS-1 phosphorylation and insulin induced Akt activation by Ang II were examined in clone 9 ( C9 ) hepatocytes
González-Rodríguez et al., Diabetes 2010 : The absence of PTP1B in the double-mutant mice restored hepatic IRS1 mediated phosphatidylinositol (PI) 3-kinase/Akt/Foxo1 signaling ... Moreover, resveratrol treatment of hyperglycemic IRS2 ( -/- ) mice decreased hepatic PTP1B mRNA and inhibited PTP1B activity, thereby restoring IRS1 mediated PI 3-kinase/Akt/Foxo1 signaling and peripheral insulin sensitivity
Jain et al., Mol Nutr Food Res 2010 (Diabetes Mellitus, Type 2...) : While CDN and CP had no effect, activation of NFkappaB, Akt and glucose transporter-2 levels were decreased, insulin receptor substrate 1 (IRS-1) activation increased in livers of CDNC-rats ... CDNC is a potent hypoglycemic compound with anti-inflammatory activity apparently mediated by elevated blood vitamin C and adiponectin and inhibition of NFkappaB, Akt , and Glut-2 and increased IRS-1 activation in livers of type 2 diabetic rats
Leng et al., J Endocrinol 2010 (Insulin Resistance) : In contrast to the insulin induced degradation of IRS1, HG-induced degradation of IRS1 did not require IR signaling or phosphatidylinositol 3-kinase/Akt activity
Bu et al., J Endocrinol 2010 : Our results showed that IRS1 short hairpin RNAs can effectively suppress the expression of IRS1, and inhibit the phosphorylation of AKT in IRS1 pathway ; reduce the expression of MMP2, MMP3, MMP13, and MMP14, decrease the expression of TNFRSF11B and RANKL ( also known as tumor necrosis factor ( ligand ) superfamily, member 11 ), however increase the RANKL/TNFRSF11B ratio ; decrease cell survival, proliferation, and mineralization, and impair the differentiation of MC3T3-E1 cells
Cleveland-Donovan et al., Endocrinology 2010 (Obesity) : Over-expression of IRS-1 by lentivirus in omental preadipocytes increased IGF-I stimulated AKT-serine ( 473 ) phosphorylation
Rueda-Clausen et al., Diabetes 2011 (Anoxia...) : These changes in lipid homeostasis were accompanied by in vivo insulin resistance and impaired glucose tolerance and associated with increased phosphorylation of protein kinase C, inhibition of insulin receptor substrate 1 , and a decreased activation of protein kinase B ( PKB ; also known as Akt ) in liver and skeletal muscle in response to insulin
Badin et al., Diabetes 2011 (Insulin Resistance) : ATGL overexpression reduced insulin stimulated glycogen synthesis ( -30 %, P < 0.05 ) and disrupted insulin signaling at Ser1101 of the insulin receptor substrate-1 and downstream Akt activation at Ser473
Sugita et al., Metabolism 2012 (Burns...) : The increase of iNOS expression paralleled the increase of insulin resistance, as evidenced by decreased tyrosine phosphorylation of IR and IRS-1 , IRS-1 expression, insulin stimulated activation of phosphatidylinositol 3-kinase and Akt/PKB , and insulin stimulated glucose uptake in mouse skeletal muscle ... The increase of iNOS expression paralleled the increase of insulin resistance, as evidenced by decreased tyrosine phosphorylation of IR and IRS-1 , IRS-1 expression, insulin stimulated activation of phosphatidylinositol 3-kinase and Akt/PKB , and insulin stimulated glucose uptake in mouse skeletal muscle
Maeno et al., J Biol Chem 2012 (Metabolic Diseases) : Thr-86 of p85/PI3K was identified to be phosphorylated by PKC activation and confirmed to affect IRS1 mediated activation of Akt/eNOS by insulin and VEGF using a deletion mutant of the Thr-86 region of p85/PI3K
Battiprolu et al., J Clin Invest 2012 (Body Weight...) : Furthermore, we found that FoxO1 dependent downregulation of IRS1 resulted in blunted Akt signaling and insulin resistance
Geetha et al., J Endocrinol 2012 (Diabetes Mellitus, Type 2...) : These results indicate that PPP1R12A and PP1cd are new members of the insulin stimulated IRS1 signaling complex, and the interaction of PPP1R12A and PP1cd with IRS1 is dependent on Akt and mTOR/raptor activation
Stamper et al., Physiol Genomics 2012 (Craniosynostoses) : In subtype B, decreased phosphorylation of IRS1 ( ser-312 ) as well as increased phosphorylation of Akt ( ser-473 ), GSK3ß ( ser-9 ), IGF1R ( tyr-1135/tyr-1136 ), JNK ( thr-183/tyr-187 ), p70S6K ( thr-412 ), and pRPS6 ( ser-235/ser-236 ) was observed, thus implicating the activation of IRS1 mediated Akt signaling in potentiating craniosynostosis in this subtype
Zhou et al., Diabetes Metab 2012 (Insulin Resistance...) : NOD1 activation weakened insulin signal transduction as revealed by increased JNK and IRS-1 Ser307 phosphorylation, inhibited IRS-1 tyrosine phosphorylation, and reduced insulin induced phosphorylation of Akt on Ser473 and Thr308 in human adipocytes
Miegueu et al., Am J Physiol Gastrointest Liver Physiol 2013 : These SP effects were accompanied by downregulation of insulin receptor substrate 1 ( -82 ± 2 %, P < 0.01 ) and GLUT4 ( -76 ± 2 %, P < 0.01 ) mRNA expression, and SP acutely blocked insulin mediated stimulation of fatty acid uptake and Akt phosphorylation
Brandner et al., Toxicology 2013 (Liver Neoplasms, Experimental) : By `` working upwards '' from mTOR, we observed that TCDD inhibited endogenous and IGF-I induced AKT and ERK activation by interfering with tyrosine phosphorylation of insulin receptor substrate 1
Hao et al., Cancer Cell 2013 (Neoplasms) : Disruption of the IRS1-p110a E545K interaction destabilizes the p110a protein, reduces AKT phosphorylation, and slows xenograft tumor growth of a cancer cell line expressing p110a E545K
Sharma et al., Mol Cell Biol 1997 : In 3T3-L1 adipocytes, interference with the IR-IRS-1 interaction did not cause inhibition of insulin stimulated AKT activation or glucose transport