Disease relevance of IGF1R

• A single patient with Beckwith-Wiedemann Syndrome (BWS) demonstrated monoallelic expression of the maternally derived IGF1R allele in normal kidney, associated Wilms' tumour and in peripheral blood lymphocytes [1].
• We have previously shown that a chimeric single-chain antibody against IGF1R (scFv-Fc) and a murine antibody EM164 down-regulate IGF1R, making breast cancer cells unresponsive to IGF-I [2].
• In four cases, IGF1R and IRS-1 levels were lower in the metastases than in the primary tumors [3].
• The IGF1R was significantly up-regulated at the protein and mRNA level in primary prostate cancer compared with benign prostatic epithelium [3].
• Transgenic mice overexpressing IGF1R in the heart displayed cardiac hypertrophy, which was the result of an increase in myocyte size, and there was no evidence of histopathology [4].
• To validate the IGF1R pathway as a potential target in MPNSTs, we first confirmed that high IGF1R protein correlated with worse tumor-free survival in an independent set of samples using IHC [5].

Psychiatry related information on IGF1R

• Association of insulin-like growth factor-1 receptor polymorphism in dementia [6].
• 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 [7].
• Insulin-like growth factor-I receptor densities in human frontal cortex and white matter during aging, in Alzheimer's disease, and in Huntington's disease [8].

High impact information on IGF1R

• IGF-1 receptor regulates lifespan and resistance to oxidative stress in mice [9].
• Regulation of vascular endothelial growth factor-dependent retinal neovascularization by insulin-like growth factor-1 receptor [10].
• The close correspondence between an approximate 50% effective dose (ED50) of phosphorylation and an approximate Kd for IGF-I binding leads us to conclude that a high-affinity IGF-I receptor, not the structurally similar insulin receptor, is the mediator of IGF-I stimulated kinase activity [11].
• The insulin and IGF-I receptor proteins, like the receptor proteins for other growth-promoting hormones such as EGF and PDGF, are closely associated with tyrosine-specific protein kinase activities [12].
• A new view of neurodegeneration has recently emerged in which a TNF receptor induces death through the 'silencing of survival signals' (SOSS), such as phosphatidylinositol 3' kinase (PI3 kinase), that are activated by the insulin-like growth factor 1 receptor [13].

Chemical compound and disease context of IGF1R

• The clinical importance of these epigenetic and genetic changes has recently been stressed by the finding that IGF1R signaling alters the apoptotic response of breast cancer cells to genotoxic stress and, in addition, IGF1R activation sensitizes cells to estrogen by inducing phosphorylation of the estrogen receptor [14].
• The increase in the transcription of IGF2 and IGF1R in IUGR term placentas may represent a counter regulatory mechanism in response to the growth retardation [15].
• IGF-1 receptor tyrosine kinase inhibition by the cyclolignan PPP induces G2/M-phase accumulation and apoptosis in multiple myeloma cells [16].
• To explore the impact of inhibition of Y1136 on Akt phosphorylation we transfected P6 cells (overexpressing IGF-1R) and malignant melanoma cells with different IGF-1R mutants, including Y1136F (tyrosine replaced by phenylalanine) [17].
• Insulin-like growth factor-I receptor signaling in tamoxifen-resistant breast cancer: a supporting role to the epidermal growth factor receptor [18].

Biological context of IGF1R

• These findings challenge earlier reports of IGF1R down-regulation in metastatic disease and reinforce the importance of the IGF1R in prostate cancer biology [3].
• The type 1 insulin-like growth factor receptor (IGF1R) mediates tumor cell growth, adhesion, and protection from apoptosis [3].
• Our data show that IGF1R can regulate several aspects of the malignant phenotype [19].
• The type 1 insulin-like growth factor receptor (IGF1R) is required for growth, tumorigenicity and protection from apoptosis [20].
• OBJECTIVE: We studied clinical and in vitro aspects of a human IGF1R gene dosage effect [21].

Anatomical context of IGF1R

• Furthermore, expression levels of IGF1R were significantly decreased, and p38 was aberrantly phosphorylated in marrow stromal cells from AtmKO mice [22].
• In breast cancer, we have previously shown that insulin-like growth factor I (IGF-I) enhances cell motility in the highly metastatic MDA-231BO cell line by activating the type I IGF receptor (IGF1R) [23].
• Transcripts for all three receptors (insulin receptor, IGF1R, IGF2R) were present in human oocytes and preimplantation embryos [24].
• In contrast to odontoclasts, cementoblasts and periodontal ligament (PDL) fibroblasts carried IGF1R [25].
• PDL fibroblasts showed immunostaining for the IGF1R [26].

Associations of IGF1R with chemical compounds

• However, IGF1R gene silencing was capable of inducing significant inhibition of survival, enhancement of apoptosis, and approximately two-fold sensitization to cisplatin and temozolomide [27].
• The type 1 IGF receptor (IGF1R) is a transmembrane tyrosine kinase that is frequently overexpressed by tumours, and mediates proliferation and apoptosis protection [28].
• In both DU145 and PC3, IGF1R knockdown led to enhancement of sensitivity to mitoxantrone, etoposide, nitrogen mustard and ionizing radiation [29].
• Disruption of IGF-II/IGF1R interaction appears to be the main mode of action of suramin since the suramin response was abolished in the presence of the IGF1R blocking antibody, alpha IR-3 [30].
• Two alternatively spliced IGF1R mRNA transcripts have been described to differ by only three nucleotides (CAG) in the coding sequence, resulting in an amino-acid change from the originally described Thr-Gly to an Arg in the extracellular portion of the receptor beta subunit [31].
• Fibronectin-induced adhesion is mediated through beta1 integrin receptor and is IGF-IR-independent [32].

Physical interactions of IGF1R

• These data suggest that the positive charges in the C- and D-regions of IGF-1 contribute significantly to the binding preference of the IGF-1R for IGF-1 [33].
• We conclude that SOCS-3 binds to the IGFIR and may be a direct substrate for the receptor tyrosine kinase [34].
• Furthermore IGF-binding proteins are specific for IGF-I and IGF-II thereby modulating the binding of the IGFs to the IGF-I receptor [35].
• In addition, IGF1R down-regulation increased insulin binding consistent with the formation of an increased number of holo-IR on the cell surface [36].
• RACK1 also interacted with the IGF-1R in fibroblasts and MCF-7 cells and with endogenous insulin receptor in COS cells [37].

Enzymatic interactions of IGF1R

• TNF-alpha and IL-1beta act by inhibiting the IGF-I receptor from tyrosine phosphorylating insulin receptor substrate-1 without affecting tyrosine kinase activity of the IGF-IR itself [38].
• Notably, IL-1beta suppresses the ability of the IGF-I receptor tyrosine kinase to phosphorylate its major docking protein, insulin receptor substrate-1, in MCF-7 breast carcinoma cells [39].

Regulatory relationships of IGF1R

• We previously showed that IGF1R knockdown blocked survival of prostate cancer cells in which Akt activation was deregulated by PTEN loss [27].
• Luteolin inhibited insulin-like growth factor 1 (IGF-1) induced activation of IGF-1R and AKT in prostate cancer PC-3 and DU145 cells [40].
• We found that human SOCS-3 protein interacts directly with the cytoplasmic domains of the activated IGFIR and the insulin receptor (IR) in the yeast two-hybrid assay [34].
• To mimic IGF-1R expression levels in CD28-stimulated Jurkat cells these cells were stably transfected to over-express the IGF-1R [41].
• In a yeast two-hybrid screen of a human fetal brain library, we have previously identified SOCS-2 as a binding partner of the activated IGF-I receptor (IGFIR) [34].

Other interactions of IGF1R

• Around midgestation a separate IGF-1 receptor, indicated by the preferential displacement of iodinated IGF-1 by IGF-1, appeared [42].
• Shc immunoprecipitates performed after IGF-1 stimulation contain coprecipitated EGFR, suggesting that IGF-1R activation induces the assembly of EGFR.Shc complexes [43].
• 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 [33].
• In HCA7 colon and C4-2 prostate carcinoma cells, ERBB2 is constitutively activated in a ligand-independent manner, whereas IGF1R-beta and PDGFR-beta require ligand interaction for activation [44].
• {beta}-Arrestin is crucial for ubiquitination and down-regulation of the insulin-like growth factor-1 receptor by acting as adaptor for the MDM2 E3 ligase [45].

Analytical, diagnostic and therapeutic context of IGF1R

• IGF1R-overexpressing MCF7 xenografts in nude mice were visualized at 4, 12, and 24 h after tail vein administration of the (99m)Tc-CCND1 antisense probe but not the control probe [46].
• It will be important to use data from preclinical and early clinical trials to establish the molecular correlates of sensitivity to IGF1R blockade, and the optimum means of combining this new approach with standard treatment modalities [28].
• Although multiple receptors for the IGFs have been identified, the IGFs primarily exert their biologic effects through ligation of the type I IGF receptor tyrosine kinase (IGF1R) [47].
• In this study, we examine the relative expression of the two IGF1R mRNA isoforms by a semiquantitative RT-PCR approach using highly standardized conditions, beta-2 microglobulin (B2M) as a reference gene and gel imaging analysis [31].
• Scatchard analysis revealed 3- and 5-fold increases in IGF-1R expression by the primary cervical cancer cell cultures and cervical cancer cell lines, respectively, compared with the normal ectocervical cells [48].

References