Disease relevance of Igf1r

• In contrast, null mutants for the Igf1r gene die invariably at birth of respiratory failure and exhibit a more severe growth deficiency (45% normal size) [1].
• Igf-1(-/-)/Igf1r(-/-) double mutants did not differ in phenotype from Igf1r(-/-) single mutants, while in Igf-2(-)/Igf1r(-/-) and Igf-1(-/-)/Igf-2(-) double mutants, which are phenotypically identical, the dwarfism was further exacerbated (30% normal size) [1].
• beta-cell-specific deletion of the Igf1 receptor leads to hyperinsulinemia and glucose intolerance but does not alter beta-cell mass [2].
• Surface IR and IGF-1R expression, measured by flow cytometry, demonstrated that the MM cell lines expressed more IRs and IGF-1Rs than did the EBV, Ramos, or HS Sultan cell lines [3].
• To further define the role of insulin-like growth factor-1 (IGF-1) and its receptor (IGF-1R) in osteosarcoma (OS), human OS cell lines with low (SAOS-2) and high (SAOS-LM2) metastatic potential and three canine OS-derived cell lines were studied [4].

Psychiatry related information on Igf1r

• In rodents, IGF-I receptor impairment led to brain amyloidosis, cognitive disturbance, and hyperphosphorylated tau deposits together with other changes found in Alzheimer's disease such as gliosis and synaptic protein loss [5].

High impact information on Igf1r

• To directly define the role of Igf1, we have created a mouse with a beta-cell-specific knockout of Igf1r (betaIgf1r(-/-)) [2].
• Irs-2 coordinates Igf-1 receptor-mediated beta-cell development and peripheral insulin signalling [6].
• In addition to generalized organ hypoplasia in Igf1r(-/-) embryos, including the muscles, and developmental delays in ossification, deviations from normalcy were observed in the central nervous system and epidermis [1].
• The Igf1r(+/-) mice display greater resistance to oxidative stress, a known determinant of ageing [7].
• The ability of the insulin receptor to act as a bona fide IGF-II-dependent growth promoter is underscored by its rescue of double knockout Igf1r/Igf2r mice [8].

Chemical compound and disease context of Igf1r

• To investigate insulin-like growth factor I (IGF-I) and IGF-I receptor gene expression during experimental demyelination and myelin regeneration, young mice were fed cuprizone (( bis(cyclohexanone) oxaldihydrazone )) [9].
• The androgen-independent human prostate adenocarcinoma cell line DU-145 proliferates in serum-free medium and produces insulin-like growth factors (IGF)-I, IGF-II, and the IGF type-1 receptor (IGF-1R) [10].
• Now IGF-1R, the receptor tyrosine kinase for IGF-II, has been found to be variably upregulated, first uniformly in dysplastic and angiogenic progenitors and then focally at the margins and in invasive regions of carcinomas [11].
• Herein, we extend our analyses to examine the impact of insulin/IGF-1 receptor inhibition on primary hepatocyte survival when exposed to the secondary bile acid deoxycholic acid (DCA) and compare the impact inhibition of this receptor has on bile acid toxicity effects to that of ERBB1/MEK1/2 inhibition [12].
• In MCF-7 human breast cancer cells, low micromolar concentrations of NDGA inhibited activation of the IGF-1R, and downstream phosphorylation of both the Akt/PKB serine kinase and the pro-apoptotic protein BAD [13].

Biological context of Igf1r

• We also examined the effect of heterozygous null Igf1r mutations on glucose homeostasis in adult mice [14].
• Here, we report the mapping of mouse Igf1r to mouse chromosome 7 (MMU7) by somatic cell hybrid analysis [15].
• The insulin-like growth factor 1 receptor (IGF-1R) is a multifunctional receptor that mediates signals for cell proliferation, differentiation, and survival [16].
• This indicated that most, if not all, of the estradiol-stimulated Tyr phosphorylation of uterine IRS-1 originates from ligand activation of IGF-1R kinase [17].
• Susceptibility to apoptosis in insulin-like growth factor-I receptor-deficient brown adipocytes [18].

Anatomical context of Igf1r

• Fibroblast cell lines were established from mouse embryos homozygous for a targeted disruption of the Igf1r gene, encoding the type 1 receptor for insulin-like growth factor I (IGF-I) and from their wild-type littermates [19].
• To examine the local actions of IGF signaling in skeletal tissue in a physiological context, we have used Cre-mediated recombination to disrupt selectively in mouse osteoblasts the gene encoding the type 1 IGF receptor (Igf1r) [20].
• Here we show that the insulin receptor tyrosine kinase family, comprising Ir, Igf1r and Irr, is required for the appearance of male gonads and thus for male sexual differentiation [21].
• Since hormonal activation of IRS-1 is epithelial, estrogen-specific, and initiated before maximal DNA synthesis occurs following treatment with hormone, this protein, as part of the IGF-1R pathway, may be important in mediating estrogen-stimulated proliferation in the uterus [22].
• Furthermore, IGF-1R-null keratinocytes exhibit accelerated differentiation and decreased proliferation [16].

Associations of Igf1r with chemical compounds

• The nonestrogenic steroid hormones examined did not stimulate the P-Tyr content of IGF-1R or IRS-1 [22].
• In streptozotocin-induced diabetes, IGF-I receptor was up-regulated in the kidneys from decorin-null mice [23].
• We conclude that the insulin receptor mediates some aspects of metabolic signaling in adipocytes more effectively than the IGF-I receptor, as a consequence of more efficient phosphorylation of IRS-1 and greater recruitment/activation of phosphoinositide 3-kinase [24].
• In contrast, Zn(2+) increases the affinity by which either [(125)I]-IGF-I or [(125)I]-R(3)-IGF-I binds to the IGF-1R, but depresses [(125)I]-IGF-II binding to the IGF-type 2 receptor (IGF-2R) on BC(3)H-1 cells [25].
• In addition, to determine whether IGF-II decreases IGF-I receptor expression by stimulating receptor protein degradation, pulse/chase experiments with [35S]methionine/cysteine were carried out [26].

Physical interactions of Igf1r

• In contrast, the C and D domains of IGF-I allow higher affinity binding to the IGF-1R than the analogous domains of IGF-II [27].
• In contrast, Zn(2+) increased IGF-I, IGF-II and R(3)-IGF-I binding to the IGF-1R by increasing ligand binding affinity on both P(2)A(2a)-LISN and L6 myoblasts [28].
• In 3T3-L1 cells, IGF-1 receptor is located in lipid rafts/caveolae of the plasma membrane and can directly interact with caveolin-1, the major protein component in caveolae [29].

Enzymatic interactions of Igf1r

• As a result, the affinity constants of IRS-1 to phosphorylated and unphosphorylated IGF-1R were (8.06+/-5.18)x10(9) M(-1) and (9.81+/-4.61)x10(8) M(-1), respectively [30].
• Levels of insulin-like growth factor-I receptor and phosphorylated Akt were reduced by MSA [31].

Regulatory relationships of Igf1r

• In these cells, insulin stimulated IR homodimer phosphorylation, whereas IGF-I activated both IGF-I receptor homodimers and hybrid receptors [32].
• c-myc-induced hepatocarcinogenesis in the absence of IGF-I receptor [33].
• Transfection of GHo cells with a dominant negative IGF-1R mutant construct blocked the generation of NO and activation of Akt seen in GHo cells compared to vector alone control EL4 cells [34].
• Collectively, these findings suggest that SOCS1 suppresses muscle differentiation through negative feedback regulation of IGF-I receptor-mediated signaling [35].
• Quantitative double-label immunocytochemistry studies showed that GnRH perikarya expressed IGF-1R [36].

Other interactions of Igf1r

• Preimplantation parthenogenetic mouse embryos expressed mRNA for the IGF-II receptor but not for either IGF-II ligand or the IGF-I receptor, indicating that the latter genes are not expressed when inherited maternally [37].
• Thus, protein kinase B/Akt 1 is an important signal mediator in IGF-1 receptor signal cascade for inducing adipocyte differentiation [38].
• Unlike the liver, which is mostly unaffected by changes in IGF-I level, skeletal muscles express high levels of IGF-I receptor (IGF-IR) [39].
• RESULTS: IGF-1 and IGF binding protein 2 (IGFBP-2) mRNA were rapidly reduced whereas IGFBP-3 and IGF-R1 mRNA were increased after castration [40].
• These results suggest that Meg1/Grb10 inhibits the function of both insulin and IGF1 receptors in these cells, since a similar phenotype has been reported for Ir and Igf1r double knockout mice [41].

Analytical, diagnostic and therapeutic context of Igf1r

• This is the first study to give a complete overview of the mRNA expression patterns of Igf-1, Igf-2, type 1 Igf receptor (Igf1r) and six Igf binding proteins (IGFBP-1-6) in embryonic mouse limbs, at various stages of development, by whole mount in situ hybridization (ISH) [42].
• By using a combined approach of conditional gene ablation and a three-dimensional organotypic model, we demonstrate that IGF-1R-deficient skin cocultures show abnormal maturation and differentiation patterns [16].
• The IGF-1 receptor was detected immunohistochemically with antibodies to the IGF-1 receptor and visualized with conventional light microscopy and confocal laser scanning microscopy (CLSM) [43].
• An increase in the expression of the IGF-1R in GHo cells was also detected by Western blot analysis, (125)I-IGF-1 binding and analysis of IGF-1R promoter luciferase constructs [34].
• The absence of IGF-1R caused a significant decrease in hepatocyte proliferation in males (-52%), but not in females, as assessed by Ki67 immunohistochemistry [44].

References