The insulin-like growth factor type 1 receptor (IGF-1R) plays a key role in the development and progression of cancer; however, therapeutics targeting it have had disappointing results in the clinic. As a receptor tyrosine kinase (RTK), IGF-1R is traditionally described as an ON/OFF system, with ligand stabilizing the ON state and exclusive kinase-dependent signaling activation. Newly added to the traditional model, ubiquitin-mediated receptor downregulation and degradation was originally described as a response to ligand/receptor interaction and thus inseparable from kinase signaling activation. Yet, the classical model has proven over-simplified and insufficient to explain experimental evidence accumulated over the last decade, including kinase-independent signaling, unbalanced signaling, or dissociation between signaling and receptor downregulation. Based on the recent findings that IGF-1R “borrows” components of G-protein coupled receptor (GPCR) signaling, including β-arrestins and G-protein-related kinases, we discuss the emerging paradigm for the IGF-1R as a functional RTK/GPCR hybrid, which integrates the kinase signaling with the IGF-1R canonical GPCR characteristics. The contradictions to the classical IGF-1R signaling concept as well as the design of anti-IGF-1R therapeutics treatment are considered in the light of this paradigm shift and we advocate recognition of IGF-1R as a valid target for cancer treatment.

These findings strongly suggest that this mutation leads to failure of processing of the IGF-IR proreceptor to mature IGF-IR and causes short stature and IUGR.

Metformin decreases endogenous glucose production by the liver. Few studies have examined the effect of metformin on the insulin-signaling pathway in liver models, and none have presented data on the effect in normal human liver. Huh7 human hepatoma cells and primary human hepatocytes were used. Insulin receptor (IR) and IR substrates (IRS)-1 and -2 were assessed by immunoprecipitation and immunoblot. Normal human liver was used to assay IR kinase activity (IR-KA). Tyrphostin AG1024 was used to inhibit IR-KA and examine effects on deoxyglucose uptake. Metformin (1 micro g/ml) increased IR tyrosine phosphorylation by 78% (P = 0.0007) in 30 min in human hepatocytes and Huh7 cells and increased IRS-2 but not IRS-1 activation, and the downstream increase in deoxyglucose uptake was mediated via increased translocation of GLUT-1 to the plasma membrane. Metformin did not augment maximal or submaximal insulin-stimulated IR activation. Metformin increased basal IR-KA by 150% (P = 0.0001). AG1024 inhibited metformin-induced IR-beta phosphorylation in a concentration-dependent manner and abolished metformin-induced 2-deoxyglucose uptake. This study demonstrates that the mechanism of action of metformin in liver involves IR activation, followed by selective IRS-2 activation, and increased glucose uptake via increased GLUT-1 translocation. The effect of metformin was completely blocked by an IR inhibitor.

The type 1 IGF receptor (IGF1R) is required for normal embryonic and postnatal growth. The aim of this study was to determine whether we could detect abnormal IGF1R function in skin fibroblasts from children with an abnormal copy number of the IGF1R gene. We report two children with altered copy number of the IGF1R gene who presented with abnormal growth. Case 1 is a girl with intrauterine growth retardation, postnatal growth failure, and recurrent hypoglycemia. Pituitary function tests were normal. Routine karyotype analysis identified a deletion on 15q26.2, and a fluorescence in situ hybridization study using IGF1R probes showed only a single IGF1R gene. Case 2 was large for gestational age, with birth weight and length at or above 97th percentile, and showed rapid early postnatal growth. He was found to have a recombinant chromosome 15 containing a partial duplication at 15q (q25-qter). A fluorescence in situ hybridization study using the same probes showed three copies of the IGF1R gene. In a mitochondrial activity assay, skin fibroblasts from the subject with only one copy of IGF1R showed slower growth, whereas cells from the subject with three copies of IGF1R showed accelerated growth compared with controls. IGF1R phosphorylation, as assessed by Western blot, and IGF1R binding studies were decreased compared with controls in the child with one copy of the IGF1R and increased in the child with three copies of the gene. Our data are consistent with the concept that IGF1R gene copy number is of functional and clinical importance in humans.

Hormone or neurotransmitter signaling is mediated by transient fluctuations in intracellular cAMP within a very narrow range of concentrations (1). Maximal biological effects are elicited with only 2-3-fold changes in intracellular cAMP levels, while the cell potential for cAMP production is usually much larger. In addition, the increase in intracellular cAMP is transient despite the continuous presence of the extracellular stimulus (2, 3). This limited and short-lived nature of the activating signal is an essential feature of hormone or neurotransmitter action. This is necessary to decrease the intrinsic "noise" in the signaling mechanism, to allow iterative signaling, and to prevent excessive stimulation.The rapid and transient changes in cAMP concentrations are the result of changes in both synthesis and degradation of the second messenger cAMP, involving steps at the receptor as well as at a postreceptor level (4, 5). Following the activation of G s and adenylyl cyclase, receptor phosphorylation causes an uncoupling from G s , and therefore a decrease in cAMP synthesis. For the ␤ 2 -adrenergic receptor, ␤ 2 -adrenergic receptor kinases phosphorylate only agonist-occupied active receptors and enhance the affinity of the receptors for the inhibitor protein ␤-arrestin (6). Binding of ␤-arrestin to the phosphorylated receptors inhibits the receptor-G s interaction, thereby inducing the uncoupled or desensitized state of the receptors (7). Several kinases have also been implicated in the phosphorylation of the glycoprotein receptors including the GRK kinases, PKA 1 and PKC. While PKA efficiently phosphorylates and uncouples the ␤-adrenergic receptor (5), the involvement of this kinase in the glycoprotein receptor phosphorylation is less clear (8).In addition to receptor uncoupling from G protein and cyclase, rapid modulation of phosphodiesterases and of cAMP degradation plays an essential role in the transient accumulation of cyclic nucleotides (9). This concept was initially inferred by the use of xanthine inhibitors of PDEs and by measuring the decay of the cAMP signal in intact cells (3). The use of cAMP analogs has confirmed that cAMP-dependent PKA activation in the cell causes an activation of cAMP degradation (10 -12). The impact and physiological significance of this rapid feedback regulation is unclear.Of the many PDEs expressed in the cell, two isoforms are activated by an increase in cAMP. In platelets (13,14) and adipocytes (15, 16) a type 3 PDE is activated by a PKA-dependent phosphorylation lowering cAMP levels. Recently, a distinct PDE isoenzyme, a member of the PDE4 family, has been implicated in this feedback regulation (17). In thyroid cells, TSH causes a PKA-mediated phosphorylation and activation of a PDE4D3 variant. This conclusion is supported by studies involving PDE4-specific inhibitors and immunoprecipitation with PDE4-selective antibodies (17), and is consistent with cell-free phosphorylation and activation of the recombinant PDE4D3 enzymes (18). The site of PKA phosphorylation of PDE4D3 ...