Other entities represented in this entry:
HGNC Approved Gene Symbol: IRS1
SNOMEDCT: 44054006; ICD10CM: E11;
Cytogenetic location: 2q36.3 Genomic coordinates (GRCh38): 2:226,731,312-226,799,820 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2q36.3 | {Coronary artery disease, susceptibility to} | 3 | ||
| {Type 2 diabetes mellitus, susceptibility to} | 125853 | Autosomal dominant | 3 |
Sun et al. (1991) isolated cDNAs encoding a 160- to 185-kD phosphotyrosyl protein that was a substrate of insulin receptor tyrosine kinase and a putative participant in insulin (INS; 176730) signaling. This protein, designated insulin receptor substrate-1 (IRS1), was found in a variety of insulin-responsive cells and tissues.
Stoffel et al. (1993) cloned the IRS1 gene from a human male placenta library.
Sun et al. (1991) found that IRS1 exhibited no intrinsic enzyme activity. They suggested it serves as a docking protein involved in binding and activating other signal transduction molecules after being phosphorylated on tyrosine by insulin receptor kinase.
Binding of insulin to its receptor induces phosphorylation of the cytosolic substrates IRS1 and IRS2 (600797), which associate with several Src homology-2 (SH2) domain-containing proteins. To identify unique IRS1-binding proteins, Ogihara et al. (1997) screened a human heart cDNA library with recombinant IRS1. They obtained 2 isoforms of the 14-3-3 (YWHA) protein family, namely 14-3-3-epsilon (YWHAE; 605066) and 14-3-3-zeta (YWHAZ; 601288). 14-3-3 protein has been shown to associate with IRS1 in L6 myotubes, HepG2 hepatoma cells, Chinese hamster ovary cells, and bovine brain tissue. IRS2, a protein structurally similar to IRS1, was also shown to form a complex with 14-3-3 protein using a baculovirus expression system. The amount of 14-3-3 protein associated with IRS1 was not affected by insulin stimulation but was increased significantly by treatment with okadaic acid, a potent serine/threonine phosphatase inhibitor. Peptide inhibition experiments using phosphoserine-containing peptides of IRS1 revealed that IRS1 contains 3 putative binding sites for 14-3-3 protein. Among these 3, the motif around serine-270 is located in the phosphotyrosine-binding (PTB) domain of IRS1, which is responsible for the interaction with the insulin receptor (INSR; 147670). Indeed, a truncated mutant of IRS1 consisting of only the PTB domain retained the capacity to bind to 14-3-3 protein in vivo. Ogihara et al. (1997) investigated the effect of 14-3-3 protein binding on the insulin-induced phosphorylation of IRS1. Phosphoamino acid analysis revealed that IRS1 coimmunoprecipitated with anti-14-3-3 antibody is weakly phosphorylated after insulin stimulation, on tyrosine as well as serine residues, compared with IRS1 immunoprecipitated with anti-IRS1 antibody. Thus, the authors suggested that the association with 14-3-3 protein may play a role in the regulation of insulin sensitivity by interrupting the association between the insulin receptor and IRS1.
Cell size is strongly dependent on ribosome biogenesis, which is controlled by RNA polymerase I (see 602000). The activity of this polymerase is modulated by a complex of proteins, including UBTF (600673). From experiments with mouse embryonic fibroblasts, Drakas et al. (2004) presented evidence that a nuclear complex forms between IRS1, UBTF, and phosphatidylinositol 3-kinase (PI3K; see 171834), leading to the serine phosphorylation of UBF1 and regulation of rRNA synthesis.
Shi et al. (2007) found that expression of microRNA-145 (MIRN145; 611795) in a human colorectal adenocarcinoma cell line downregulated IRS1 translation, but did not alter IRS1 mRNA levels. Downregulation of IRS1 translation by MIRN145 required the 3-prime UTR of IRS1 mRNA. Treatment of cells with MIRN145 caused growth arrest comparable to use of small interfering RNA directed against IRS1.
Using chromatin immunoprecipitation and reporter gene assays, Wu et al. (2008) showed that nuclear Irs1 bound and activated the Myc (190080), cyclin D1 (CCND1; 168461), and ribosomal DNA promoters in mouse fibroblasts in response to Igf1. In the absence of nuclear translocation, Irs1 did not localize to these promoters, and their activation was dramatically reduced. Deletion of the phosphotyrosine-binding domain of Irs1 abolished its ability to activate the Myc and cyclin D1 promoters. Activation of Myc and cyclin D1 promoters by nuclear Irs1 did not require PI3K activity.
Using poly(A) RT-PCR, Zhang et al. (2008) found that microRNA-126 (MIR126; 611767) was downregulated in human embryonic kidney (HEK293) cells and breast cancer cell lines. Overexpression of MIR126 inhibited cell growth in HEK293 and breast cancer cells by suppressing cycle cycle progression from G0/G1 to S phase. Zhang et al. (2008) identified a complementary site for MIR126 in the 3-prime UTR of IRS1, and in vitro luciferase assays confirmed that MIR126 targeted IRS1. Overexpression of MIR126 significantly decreased IRS1 protein, but not IRS1 mRNA. Knockdown of IRS1 vi short hairpin RNA decreased cell growth in HEK293 and breast cancer cells, recapitulating the effect of MIR126 overexpression.
In mouse and human lung adenocarcinoma (211980) cells, Houghton et al. (2010) found neutrophil elastase (ELANE; 130130) directly induced tumor cell proliferation at physiologic levels by gaining access to an endosomal compartment within tumor cells, where it degraded IRS1. Degradation of IRS1 was associated with increased interaction between PI3K and the potent mitogen PDGFR (173410), skewing the PI3K axis toward tumor cell proliferation. The findings identified IRS1 as a key regulator of PI3K within malignant cells.
Song et al. (2013) showed in mice that muscle-specific mitsugumin-53 (MG53; 613288) mediates the degradation of the insulin receptor and Irs1, and when upregulated causes metabolic syndrome featuring insulin resistance, obesity, hypertension, and dyslipidemia. Mg53 expression is markedly elevated in models of insulin resistance, and Mg53 overexpression suffices to trigger muscle insulin resistance and metabolic syndrome sequentially. Conversely, ablation of Mg53 prevents diet-induced metabolic syndrome by preserving the insulin receptor, Irs1, and insulin signaling integrity. Mechanistically, Mg53 acts as an E3 ligase targeting the insulin receptor and Irs1 for ubiquitin-dependent degradation, comprising a central mechanism controlling insulin signal strength in skeletal muscle. Song et al. (2013) concluded that these findings defined MG53 as a novel therapeutic target for treating metabolic disorders and associated cardiovascular complications.
Using DNA from a human-hamster somatic cell hybrid panel and PCR, Stoffel et al. (1993) mapped the IRS1 gene to chromosome 2. By fluorescence in situ hybridization, they regionalized the assignment to 2q35-q36.1. Using a genomic clone for fluorescence in situ hybridization, Nishiyama et al. (1994) localized the IRS1 gene to 2q36. Araki et al. (1993) likewise mapped the gene to this region and showed that the homologous gene is on mouse chromosome 1. Stoffel et al. (1993) also identified a simple tandem repeat DNA polymorphism useful for genetic studies. Because of its central role in the signal transduction pathway, IRS1 is a candidate for the site of the defect in insulin action seen in patients with noninsulin-dependent diabetes mellitus (NIDDM; 125853).
Laakso et al. (1994) investigated the frequency and clinical significance of variants in the coding region of the IRS1 gene in patients with NIDDM. Applying single-strand conformation polymorphism (SSCP) analysis, they found 3 amino acid substitutions among 40 Finnish patients with typical NIDDM: gly81 to arg, ser892 to gly, and gly971 to arg (147545.0002). Almind et al. (1993) had suggested that the ala512-to-pro and gly971-to-arg polymorphisms of the IRS1 gene are common in Danish patients with NIDDM. Of the 3 amino acid substitutions observed by Laakso et al. (1994), they found ser892 to gly the most 'interesting' since it abolishes one of the potential serine phosphorylation sites which is located immediately N-terminal to the only SH2-binding site of growth factor receptor-bound protein (GRB2; 108355) and thus could potentially influence some aspects of signal transduction and metabolic response to insulin. GRB2 is a protein that associates with IRS1 upon insulin-induced phosphorylation. The ser892-to-gly substitution may influence the binding of GRB2 to IRS1 and the activation of downstream insulin signaling proteins.
Rung et al. (2009) used genomewide association data from 1,376 French individuals to identify 16,360 SNPs nominally associated with type 2 diabetes and studied these SNPs in an independent sample of 4,977 French individuals. They then selected the 28 best hits for replication in 7,698 Dutch subjects and identified 4 SNPs showing strong association with type 2 diabetes. One of these, rs2943641 (P = 9.3 x 10(-12), odds ratio = 1.19), was located 500 kb upstream of the IRS1 gene. Unlike previously reported type 2 diabetes risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish, and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-hydroxykinase activity in human skeletal muscle biopsies. Rung et al. (2009) noted that rs2943641 and the common IRS1 missense polymorphism G972R (147545.0002) lie 567 kb apart and were not in linkage disequilibrium. Further analysis suggested that rs2943641 and G972R may independently influence insulin sensitivity and type 2 diabetes risk.
Insulin resistance is often associated with atherosclerotic diseases in subjects with obesity and impaired glucose tolerance. Abe et al. (1998) studied female mice homozygous for targeted disruption of the Irs1 gene and female wildtype mice that were offspring of heterozygous mice. In this nonobese animal model of insulin resistance, they found that blood pressure and plasma triglyceride levels were significantly higher than in normal mice. Impaired endothelium-dependent vascular relaxation was also observed in these mice. Furthermore, lipoprotein lipase activity was lower than in normal mice, implicating impaired lipolysis in the increase in plasma triglyceride levels under insulin-resistant conditions. Thus, insulin resistance plays an important role in the clustering of coronary risk factors that may accelerate the progression of atherosclerosis in subjects with insulin resistance.
Bohni et al. (1999) showed that chico, a Drosophila homolog of the vertebrate IRS gene family, plays an essential role in the control of cell size and growth. Animals mutant for chico were less than half the size of wildtype flies, owing to fewer and smaller cells. In mosaic animals, chico homozygous cells grew slower than their heterozygous sibs, showed an autonomous reduction in cell size, and formed organs of reduced size. Although chico flies were smaller, they showed an almost 2-fold increase in lipid levels.
Clancy et al. (2001) found that mutation of chico extends fruit fly life span by up to 48% in homozygotes and 36% in heterozygotes. Extension of life span was not a result of impaired oogenesis in chico females, nor was it consistently correlated with increased stress resistance. The dwarf phenotype of chico homozygotes was also unnecessary for extension of life span. The role of insulin/IGF signaling in regulating animal aging is therefore evolutionarily conserved.
In a review, Myers et al. (1994) pointed out that since disruption of the gene encoding Irs1 in mice is not lethal, there must be other molecules that the insulin receptor can use to regulate critical metabolic pathways.
Kulkarni et al. (1999) found that freshly isolated islets from Irs1 knockout mice and SV40-transformed Irs1-deficient beta-cell lines exhibited marked insulin secretory defects in response to glucose and arginine. Furthermore, insulin expression was reduced by about 2-fold in the Irs1-null islets and beta-cell lines, and this defect could be partially restored by transfecting the cells with Irs1. These data provided evidence for an important role of IRS1 in islet function and for a novel functional link between the insulin signaling and insulin secretion pathways.
Type II diabetes (NIDDM) is characterized by abnormalities of insulin action in muscle, adipose tissue, and liver and by altered beta-cell function. To analyze the role of the insulin signaling pathway in these processes, Kido et al. (2000) generated mice with combined heterozygous null mutations in the insulin receptor, insulin receptor substrate-1, and/or insulin receptor substrate-2 (Irs2; 600797). Diabetes developed in 40% of animals heterozygous for all 3 null mutations, 20% of those heterozygous for the Insr/Irs1 null mutations, 17% of those heterozygous for the Insr/Irs2 mutations, and 5% of those heterozygous for the null mutation of Insr only. Although combined heterozygosity for Insr/Irs1 null mutations and Insr/Irs2 null mutations resulted in a similar number of diabetic mice, there were significant differences in the underlying metabolic abnormalities. Mice of the Insr/Ins1 double heterozygosity developed severe insulin resistance in skeletal muscle and liver, with compensatory beta-cell hyperplasia. In contrast, mice of the Insr/Ins2 double heterozygosity developed severe insulin resistance in liver, mild insulin resistance in skeletal muscle, and modest beta-cell hyperplasia. Triple heterozygotes developed severe insulin resistance in skeletal muscle and liver and marked beta-cell hyperplasia. These data indicated tissue-specific differences in the IRSs to mediate insulin action, with Irs1 playing a prominent role in skeletal muscle and Irs2 in liver. They also provided a practical demonstration of the polygenic and genetically heterogeneous interactions underlying the inheritance of type II diabetes.
Mice homozygous for lack of the IRS1 gene show severe osteopenia with low bone turnover. IRS1 is expressed in osteoblasts, but not in osteoclasts, of wildtype mice. Ogata et al. (2000) showed that osteoblasts from homozygous deficient mice treated with insulin or IGF1 (147440) failed to induce tyrosine phosphorylation of cellular proteins and showed reduced proliferation and differentiation. Osteoclastogenesis in the coculture of hemopoietic cells and osteoblasts depended on IRS1 expression in osteoblasts and could not be rescued by IRS1 expression in hemopoietic cells in the presence not only of IGF1 but also 1,25(OH)2D3. Ogata et al. (2000) concluded that IRS1 deficiency in osteoblasts impairs osteoblast proliferation, differentiation, and support of osteoclastogenesis, resulting in low-turnover osteopenia. Ogata et al. (2000) concluded further that osteoblastic IRS1 is essential for maintaining bone turnover, because it mediates signaling by IGF1 and insulin and, they proposed, also by other factors, such as 1,25(OH)2D3.
Using hyperinsulinemic-euglycemic clamps, Kim et al. (2004) demonstrated that skeletal muscle and hepatic insulin action did not differ between wildtype and Pkc-theta (600448) null mice. A 5-hour lipid infusion decreased insulin-stimulated skeletal muscle glucose uptake in the wildtype mice that was associated with 40 to 50% decreases in insulin-stimulated tyrosine phosphorylation of insulin receptor substrate-1 and IRS1-associated PI3K activity. In contrast, Pkc-theta inactivation prevented fat-induced defects in insulin signaling and glucose transport in skeletal muscle. Kim et al. (2004) concluded that PKC-theta is a crucial component mediating fat-induced insulin resistance in skeletal muscle.
The article by Taniguchi et al. (2005) reporting results of the knockdown of Irs1, Irs2, or both in mice was retracted 'at the request of the corresponding author' because of duplications found in some of the figures.
Using genomic DNA as a template, Esposito et al. (1996) performed SSCP analysis of the region of the IRS1 gene spanning codons 624-755 in 63 unrelated NIDDM (125853) patients and in 47 control subjects. A unique conformer was found in 1 NIDDM patient: a deletion of 1 of the 2 GGT direct repeats at codons 722 and 723 in one IRS1 allele. The nucleotide change was predicted to result in deletion of gly723 from the protein product. Several lines of evidence suggested to Esposito et al. (1996) that the amino acid deletion may have affected the function of insulin receptor substrate-1. Gly723 is conserved in IRS1 sequences from human muscle, human hepatoma, mouse, and rat, and lies 9 amino acids upstream from 1 of the YMNM motifs. Family members were not available for study. Gly723del was not thought to be a common polymorphism as it was detected in only 1 of 220 chromosomes screened (126 chromosomes from unrelated NIDDM patients and 94 from normoglycemic subjects).
The most frequent IRS1 variant is gly972 to arg (G972R), and the arg972 variant is twice as prevalent in patients with type II diabetes (NIDDM; 125853) as in control subjects. Various data suggest that the single molecular defect in insulin signaling, involving the defective interaction between phosphatidylinositol 3-kinase (PI3K; see 171834) and IRS1, might result in both peripheral insulin resistance (see 125853) and impaired insulin secretion. Carriers of the arg972 variant show lower fasting insulin and C-peptide levels compared with noncarriers. For example, Clausen et al. (1995) described a young, healthy, lean male homozygous for the arg972 variant who had low fasting plasma insulin levels and a low acute insulin response. To investigate directly whether the polymorphism in codon 972 of the IRS1 gene impairs insulin secretion, Porzio et al. (1999) overexpressed both wildtype IRS1 and the arg972 IRS1 variant in cultured cells. The arg972 variant did not affect expression or function of endogenous IRS2 (600797). Cultured cells expressing the arg972 variant exhibited a marked decrease in both glucose- and sulfonylurea-stimulated insulin secretion compared with wildtype cells. Porzio et al. (1999) suggested that the common arg972 IRS1 polymorphism may impair glucose-stimulated insulin secretion, thus contributing to the relative insulin deficiency observed in carriers of this variant. (Almind et al. (1993) referred to the gly972-to-arg mutation as gly971 to arg.)
Almind et al. (1996) examined insulin-stimulated processes in a cultured myeloid progenitor cell line stably overexpressing the insulin receptor when transfected with either wildtype human IRS1 or the gly972-to-arg common variant (numbering according to Nishiyama and Wands, 1992). They showed that the mutation in codon 972 of the IRS1 gene impairs insulin-stimulated signaling, especially along the PI3K pathway, and may contribute to insulin resistance in normal and diabetic populations.
To determine the prevalence of variants in NIDDM candidate genes, 't Hart et al. (1999) studied random samples of subjects with NIDDM and controls from the Hoorn and Rotterdam population-based studies. A significant difference in the frequency of the G972R allele of the IRS1 gene was observed between control subjects from Hoorn and Rotterdam.
Baroni et al. (1999) investigated the role of the G972R mutation in predisposition to coronary artery disease (CAD). They studied the DNA of 318 subjects with angiographically documented coronary atherosclerosis (greater than 50% stenosis) and 208 population control subjects. The frequency of the G972R mutation was 18.9% in CAD patients and 6.8% in controls (less than 0.001). After controlling for other coronary risk factors, the relative risk of CAD associated with the G972R mutation was 2.93 in the entire cohort. The risk was even higher in the subgroups of obese subjects and those with clinical features of insulin resistance syndrome.
Hribal et al. (2000) overexpressed wildtype IRS1 and the arg972 IRS1 variant in L6 skeletal muscle cells and examined the functional consequences of the polymorphism on insulin metabolic signaling. Arg972 cells showed a decrease in insulin-stimulated IRS1-associated phosphatidylinositol 3-kinase (PI3 kinase) activity compared with wildtype cells as a consequence of decreased binding of the PI3 kinase p85 subunit (see 171833) to IRS1. Arg972 cells exhibited a decrease in both basal and insulin-stimulated glucose transport due to a reduction in the amount of glucose transporter-1 (GLUT1; 138140) and GLUT4 (138190) translocated to the plasma membrane. Both basal and insulin-stimulated AKT (see 164730) phosphorylations were decreased in arg972 cells compared with wildtype cells. Basal glycogen synthase kinase-3 (GSK3; see 605004) activity was increased in arg972 cells compared with wildtype cells, and insulin-induced inactivation of GSK3 was also reduced in arg972 cells. This change was associated with a significant decrease in insulin-stimulated glucose incorporation into glycogen and glycogen synthase activity in arg972 cells compared with wildtype cells. The authors concluded that the arg972 polymorphism impairs the ability of insulin to stimulate glucose transport, glucose transporter translocation, and glycogen synthesis by affecting the PI3 kinase/AKT/GSK3 signaling pathway. The data indicated that the G972R polymorphism may contribute to the in vivo insulin resistance observed in carriers of this variant.
Marini et al. (2003) investigated the relationship between the common G972R IRS1 variant and the presence of cardiovascular risk factors in 153 glucose-tolerant, unrelated offspring of type II diabetic patients. Insulin sensitivity, assessed by hyperinsulinemic-euglycemic clamp, was significantly reduced in carriers of arg972. Carriers of arg972 displayed many features of the insulin resistance syndrome, including higher values for serum triglycerides, total/high density lipoprotein cholesterol ratio, free fatty acid levels, systolic blood pressure, microalbuminuria, and intima-media thickness. These results suggested that the arg972 IRS1 variant could contribute to the risk for atherosclerotic cardiovascular diseases associated with type II diabetes by producing a cluster of insulin resistance-related metabolic abnormalities.
Abate et al. (2003) determined the frequency of the PC1 K121Q (173335.0006) and IRS1 G972R polymorphisms in Asian Indians and Caucasians and tested insulin responsiveness and glucose disposal in carriers of both polymorphisms compared to controls. (The authors referred to the IRS1 polymorphism as G972A.) The frequency of carrying at least 1 copy of the IRS1 972R variant in Asian Indians was similar to that in Caucasians (6% and 7%, respectively). IRS1 972R was not associated with any change in insulin sensitivity in the Asian Indian population studied.
In insulin-stimulated human endothelial cells from carriers of the G972R variant, Federici et al. (2004) demonstrated reduced phosphatidylinositol 3-kinase (PIK3) activity, decreased AKT and eNOS (163729)-ser1177 phosphorylation, and increased eNOS-thr495 phosphorylation compared to wildtype cells. They concluded that genetic impairment of the IRS1/PIK3/PDPK1 (605213)/AKT insulin signaling cascade results in impaired insulin-stimulated NO release and suggested that this may be a mechanism through which the G972R polymorphism contributes to the genetic predisposition to develop endothelial dysfunction and cardiovascular disease.
Perticone et al. (2004) found that human endothelial cells obtained from carriers of the arg972 IRS1 polymorphism exhibited reduced eNOS expression in response to chronic exposure to insulin. A reduction in eNOS expression would be expected to be associated with impaired endothelium-dependent vasodilation. To investigate a possible relationship between arg972 IRS1 polymorphism and endothelial dysfunction in vivo, they enrolled a cohort of 100 never-treated hypertensive subjects. Endothelium-dependent and endothelium-independent vasodilation were assessed by increasing doses of acetylcholine and sodium nitroprusside. Perticone et al. (2004) observed that acetylcholine-stimulated forearm blood flow was significantly (P less than 0.0001) lower in gly/arg heterozygous carriers than in gly/gly carriers. Sodium nitroprusside caused comparable increments in forearm blood flow in both groups. Perticone et al. (2004) concluded that, by inducing endothelial dysfunction, the arg972 IRS1 polymorphism may contribute to the genetic predisposition to develop cardiovascular disease.
Esposito et al. (2003) reported a novel thr608-to-arg (T608R) mutation in IRS1 in a patient with type II diabetes mellitus (125853). They detected the T608R mutation in 1 of 136 chromosomes from diabetic patients and in none of 120 chromosomes from nondiabetic controls, suggesting that this is a rare IRS1 variant. Conservation of thr608 in human, monkey, rat, mouse, and chicken IRS1 sequences is consistent with a crucial function for this residue. Moreover, thr608 is located near the YMXM motif containing tyr612, which is important for binding and activation of phosphoinositol 3-kinase (PI 3-kinase). When cells transfected with the IRS1 T608R mutant protein were stimulated with insulin (176730), both the amount of p85 (see 171833) coimmunoprecipitated with the mutant protein as well as the associated PI 3-kinase activity were approximately 50% less than those observed with wildtype IRS1. Moreover, in rat adipose cells, overexpression of the mutant protein resulted in significantly less translocation of GLUT4 (138190) to the cell surface than comparable overexpression of wildtype IRS1. The authors concluded that the rare IRS1 T608R mutation that may contribute to insulin resistance by impairing metabolic signaling through PI 3-kinase-dependent pathways.
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Esposito, D. L., Mammarella, S., Ranieri, A., Loggia, F. D., Capani, F., Consoli, A., Mariani-Costantini, R., Caramia, F. G., Cama, A., Battista, P. Deletion of gly723 in the insulin receptor substrate-1 of a patient with noninsulin-dependent diabetes mellitus. Hum. Mutat. 7: 364-366, 1996. [PubMed: 8723689] [Full Text: https://doi.org/10.1002/(SICI)1098-1004(1996)7:4<364::AID-HUMU13>3.0.CO;2-0]
Federici, M., Pandolfi, A., De Filippis, E. A., Pellegrini, G., Menghini, R., Lauro, D., Cardellini, M., Romano, M., Sesti, G., Lauro, R., Consoli, A. G972R IRS-1 variant impairs insulin regulation of endothelial nitric oxide synthase in cultured human endothelial cells. Circulation 109: 399-405, 2004. [PubMed: 14707024] [Full Text: https://doi.org/10.1161/01.CIR.0000109498.77895.6F]
Houghton, A. M., Rzymkiewicz, D. M., Ji, H., Gregory, A. D., Egea, E. E., Metz, H. E., Stolz, D. B., Land, S. R., Marconcini, L. A., Kliment, C. R., Jenkins, K. M., Beaulieu, K. A., Mouded, M., Frank, S. J., Wong, K. K., Shapiro, S. D. Neutrophil elastase-mediated degradation of IRS-1 accelerates lung tumor growth. Nature Med. 16: 219-223, 2010. [PubMed: 20081861] [Full Text: https://doi.org/10.1038/nm.2084]
Hribal, M. L., Federici, M., Porzio, O., Lauro, D., Borboni, P., Accili, D., Lauro, R., Sesti, G. The gly-to-arg(972) amino acid polymorphism in insulin receptor substrate-1 affects glucose metabolism in skeletal muscle cells. J. Clin. Endocr. Metab. 85: 2004-2013, 2000. [PubMed: 10843189] [Full Text: https://doi.org/10.1210/jcem.85.5.6608]
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