Disease relevance of INSR

• The mouse TRFR MAb enables transport across the tumor vasculature, which is of mouse brain origin, and the INSR MAb causes transport across the plasma membrane and the nuclear membrane of the human brain cancer cell [1].
• Mapping of the 19p13 breakpoint in an ovarian carcinoma between the INSR and TCF3 loci [2].
• Both the myotonic dystrophy (DM) and insulin receptor (INSR) genes are on chromosome 19 [3].
• Furthermore, our data suggest that risk for GDM in black and Caucasian subjects is not due to obesity perse but to interactions between obesity and INSR alleles [4].
• Mutations of insulin receptor (INSR) are causative for rare syndromes of insulin resistance and some of non insulin dependent diabetes mellitus (NIDDM) [5].

Psychiatry related information on INSR

• CONCLUSION: LTPA appears to reduce the risk of IR and IGT, an effect which is not explained by the current level of physical activity, and only partially explained by the BMI history preceding and subsequent to the assessment of LTPA [6].
• Abnormal insulin/IR levels and activities are seen in Alzheimer's dementia, whereas administration of insulin significantly improves the cognitive performance of these patients [7].
• To determine the impact of the severity of depressive symptoms on the putative association between IR and depression in young adult males, we were given access to the Northern Finland 1966 Birth Cohort database [8].
• Food deprivation induced a decrease in PTP1B and a trend toward lowered IR gene expression in LD but not in SD [9].
• The goal of this study was to further explore potential mechanisms through which diabetogenic dietary conditions that result in promotion of insulin resistance (IR), a feature of non-insulin dependant diabetes mellitus (type-2 diabetes), may influence Alzheimer's disease (AD) [10].

High impact information on INSR

• Here we demonstrate that alternative splicing of the insulin receptor (IR) pre-mRNA is aberrantly regulated in DM1 skeletal muscle tissue, resulting in predominant expression of the lower-signaling nonmuscle isoform (IR-A) [11].
• Insulin stimulates the autophosphorylation of tyrosine residues of the beta subunit of the insulin receptor (IR); this modified insulin-independent kinase has increased activity toward exogenous substrates in vitro [12].
• In vivo, these mutations not only result in a substantial decrease in insulin-stimulated IR autophosphorylation but also in a parallel decrease in the insulin-activated uptake of 2-deoxyglucose [12].
• The syndromes of insulin resistance and acanthosis nigricans. Insulin-receptor disorders in man [13].
• Restoration of HMGA1 protein expression in subjects' cells enhanced INSR gene transcription, and restored cell-surface insulin receptor protein expression and insulin-binding capacity [14].

Chemical compound and disease context of INSR

• Via activation of the IR tyrosine kinase IGF-II stimulated breast cancer cell growth [15].
• AIMS/HYPOTHESIS: We examined the properties of a mutant insulin receptor (IR) with an Arg(252) to Cys (IR(R252C)) substitution in the alpha-subunit originally identified in a patient with extreme insulin resistance and acanthosis nigricans [16].
• Furthermore, antagonists to the RTKs that are endogenously expressed in C6 glioma cells (insulin receptor (IR) and platelet-derived growth factor receptor (PDGFR)) were unable to reduce opioid-mediated ERK activation [17].
• 3. A marked association was observed between hypertension and insertion alleles of polymorphisms of the insulin receptor gene (INSR) (P < 0.0040) and the dipeptidyl carboxypeptidase-1 (angiotensin I-converting enzyme; kininase II) gene (DCP1) (P < 0.0018) [18].
• Since the main site of insulin resistance in hypertension is glycogen synthesis in skeletal muscle, genes that encode molecules involved in this pathway, i.e. insulin receptor (INSR), insulin-responsive glucose transporter (GLUT4) and glycogen synthase (GSY), were studied [19].

Biological context of INSR

• The human insulin receptor gene, INSR, and its promoter region have been isolated and characterized [20].
• INSR gene mutations have been described in multiple individuals with extreme insulin resistance, but the INSR gene has not been implicated in familial NIDDM [21].
• Pedigree members were typed for presence or absence of the Met985 substitution by hybridization of PCR-amplified exon 17 DNA to allele-specific oligonucleotide probes, and typing was confirmed by segregation of INSR haplotypes and by SSCP analysis [21].
• We previously have screened members of 18 familial NIDDM pedigrees for mutations in exons encoding the tyrosine kinase domain of the INSR gene (exons 13-21) by SSCP [21].
• Using a cloned gene probe for INSR, we have studied its linkage relationships with the DM locus and other chromosome 19 markers [3].

Anatomical context of INSR

• Insulin receptor phosphorylation, insulin receptor substrate-1 phosphorylation, and phosphatidylinositol 3-kinase activity are decreased in intact skeletal muscle strips from obese subjects [22].
• To study these pathways, we have used a myeloid progenitor cell line (32D) which is dependent on interleukin 3 but insensitive to insulin because of the very low levels of insulin receptor (IR) and the complete lack of insulin receptor substrate (IRS)-signaling proteins (IRS-1 and IRS-2) [23].
• In eight human breast cancer cell lines studied there was high affinity IGF-II binding to the IR, with subsequent IR activation [15].
• IGF-II, produced by breast cancer epithelial and stromal cells, enhances tumor growth by activating the IGF-I receptor (IGF-I-R) via autocrine and paracrine mechanisms [15].
• IGF-IR, IRS-1 and IR were expressed mainly in epithelial cells [24].

Associations of INSR with chemical compounds

• Genotypes for insulin hypervariable region (HVR), insulin-like growth factor II (IGF2), insulin receptor (INSR), and glucose transporter (GLUT1) RFLPs were studied in 96 GDM and 164 control subjects, matched to GDM for race, age, and gravidity [4].
• Insulin receptor and insulin receptor substrate (IRS)-1 serine hyperphosphorylation by an unidentified kinase(s) contributes to this defect [25].
• Previous data suggest that IR-mediated serine/threonine phosphorylation of the Ras guanine nucleotide exchange factor Sos correlates with its decreased affinity for the adapter protein Grb2 [26].
• Alanine substitution for the positively charged residues in the C- and D-regions of IGF-1 led to 15- and 10-fold losses, respectively, in binding potency for the human IGF-1R, but they increased the potency of binding to the human IR 29- and 6-fold, respectively [27].
• The effect of metformin was completely blocked by an IR inhibitor [28].

Physical interactions of INSR

• In this study, we used the sensitive two-hybrid assay of protein-protein interaction to demonstrate that SHC interacts directly with the IR [29].
• Here we demonstrate the existence of a second novel domain within Grb10 that interacts with the IR and insulin-like growth factor receptor in a kinase-dependent manner [30].
• Coimmunoprecipitation experiments and in vitro binding assays demonstrated that FLNa binds constitutively to IR and that neither insulin nor depolymerization of actin by cytochalasin D affected this interaction [31].
• However, 55PIK and SOCS-2 also interact with the IR in the yeast two hybrid system [32].
• Lastly, we show that hMAD2 can be coimmunoprecipitated with the IR from Chinese hamster ovary IR cell lysates, suggesting that this interaction occurs in vivo in cells of mammalian origin [33].

Enzymatic interactions of INSR

• We found that the SH2 domain of CSK binds to the tyrosine-phosphorylated form of IGF-IR and IR [34].
• We found that IR can directly phosphorylate FRS2 [35].
• Insulin receptor kinase phosphorylates protein tyrosine phosphatase containing Src homology 2 regions and modulates its PTPase activity in vitro [36].
• These results suggest that PTP-1B appears not only to interact with and dephosphorylate the insulin-stimulated IR in a perinuclear endosome compartment but is also involved in maintaining the IR in a dephosphorylated state during its biosynthesis [37].
• Insulin receptor beta subunit autophosphorylation occurs in an intramolecular trans-reaction in which one beta subunit phosphorylates the adjacent beta subunit within an alpha 2 beta 2 holoreceptor complex (Frattali, A. L., Treadway, J. L., and Pessin, J. E. (1992) J. Biol. Chem. 267, 19521-19528) [38].

Regulatory relationships of INSR

• Herein, we find that, in breast cancer the IR is activated by IGF-II [15].
• Furthermore, IRR mRNA was found only in cell lines that also expressed IGF-I-R mRNA [39].
• These findings provide strong evidence that alpha1,3-FucT-VII may affect insulin signaling by upregulating the phosphorylation and expression of some signaling molecules involved in the InR-signaling pathway [40].
• Plasma cell membrane glycoprotein-1 (PC-1) inhibits insulin receptor (IR) tyrosine kinase activity and subsequent cellular signaling [41].
• Here we show that Grb14 inhibits in vitro IR substrate phosphorylation [42].

Other interactions of INSR

• The SHC proteins have been implicated in insulin receptor (IR) signaling [29].
• In cultured breast cancer cells and human breast cancer specimens, the expression of AP-2 was significantly higher than that observed in cells and tissues derived from normal breast, and this overexpression paralleled the increase in IR expression [43].
• The interaction of this protein with the IR has been shown to be mediated in part by the Src homology 2 (SH2) domain of Grb10 [30].
• We observed that the IGF-IR and IR associated with the C-terminal Src kinase (CSK) following ligand stimulation [34].
• Insulin receptor activation by IGF-II in breast cancers: evidence for a new autocrine/paracrine mechanism [15].

Analytical, diagnostic and therapeutic context of INSR

• RESULT(S): After stratification of participants by body mass index, the frequency of the uncommon T allele of the INSR single nucleotide polymorphism was significantly increased in lean patients with PCOS (body mass index < or =27 kg/m2) compared with lean controls (relative risk, 2.1) [44].
• Insulin receptor (IR) and IR substrates (IRS)-1 and -2 were assessed by immunoprecipitation and immunoblot [28].
• In particular, the mRNA levels of IRR and IGF-I-R were compared by semi-quantitative RT-PCR in seven neuroblastomas and 11 soft tissue sarcomas (STS), five of which were of neuronal origin [39].
• The sequence alignments identified two cysteine residues in INSR that could be responsible for the additional disulfide bonds known to be involved in dimer formation [45].
• We applied denaturing gradient gel electrophoresis (DGGE) as well as direct sequence analysis to study the 22 exons of IR gene amplified by polymerase chain reaction (PCR) using the proband's genomic DNA as a template [46].

References