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Query: UNIPROT:P06889 (Mol)
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Insulin and insulinlike growth factor 1 (IGF-1) receptors are present in brain, yet their function remains obscure. Expression of these tyrosine kinase-bearing growth factor receptors during rat brain development was examined by using three antipeptide antibodies directed against epitopes in the beta subunits (AbP2, AbP4, and AbP5). All three antibodies recognized both insulin and IGF-1 receptors. Membranes were prepared from fetal brains (14 to 21 days of gestation), neonatal brain (postnatal day 1), and adult brain. Immunoblot analyses using AbP4 and AbP5 revealed a 92-kilodalton (kDa) protein that corresponded to the beta subunit of the insulin and IGF-1 receptors. Densitometric scanning of immunoblots indicated that receptor proteins were 4- to 10-fold more abundant in fetal brain membranes than in membranes from adult brain. Expression was highest during 16 to 18 days of gestation and declined thereafter to the relatively low level found in adult brain. Immunoblot analyses with AbP2 as well as ligand-activated receptor autophosphorylation revealed an additional protein of 97 kDa. This protein was phosphorylated in response to IGF-1 and was not directly recognized by AbP4 or AbP5. The covalent association of the 97-kDa protein with the 92-kDa beta subunit was indicated by the ability of AbP4 and AbP5 to immunoprecipitate both proteins under nonreducing conditions but only the 92-kDa protein after reduction. In contrast, AbP2 immunoprecipitated both proteins regardless of their association. This immunospecificity remained unchanged after deglycosylation of the isolated proteins. Two-dimensional tryptic phosphopeptide analysis showed that the 92- and 97-kDa subunits of the IGF-1 receptor are related but distinct proteins. Taken together, the data suggest that the 92- and 97-kDa subunits differ in primary amino acid sequence. Thus, two distinct beta subunits may be present in a single IGF-1 receptor in brain. These subunits have in common an epitope recognized by an antibody to the tyrosine kinase domain (AbP2) but differ in regions thought to be important in receptor kinase regulation and signal transduction.
Mol Cell Biol 1989 Jul
PMID:Insulin and insulinlike growth factor 1 (IGF-1) receptors during central nervous system development: expression of two immunologically distinct IGF-1 receptor beta subunits. 247 58

The testicular paracrine factor PModS is produced by peritubular myoid cells under androgen control and modulates Sertoli cell function and differentiation. The observation that luteinizing hormone (LH) stimulates inhibin production in vivo, but has no effect on isolated Sertoli cells in vitro, suggested an indirect mode of LH action, potentially mediated by PModS. The effects of the testicular paracrine factor PModS and hormones on inhibin secretion by Sertoli cells were investigated to provide insight into the endocrine control of inhibin expression. An inhibin radioimmunoassay was utilized which showed essentially parallel displacement curves with purified bovine follicular fluid inhibin, Sertoli cell conditioned medium and concentrated Sertoli cell secreted proteins. An immunoblot analysis of Sertoli cell secreted proteins with the inhibin antisera consistently detected a 32 kDa protein which is the expected size of the mature of inhibin (alpha beta) and periodically detected a 57 kDa protein which is speculated to be an incomplete processed form of the inhibin precursor (alpha 43 beta). Follicle-stimulating hormone (FSH) was found to stimulate inhibin secretion initially between days 2 and 5 of Sertoli cell culture. Insulin and retinol alone had no significant effect on inhibin secretion; however, together they appeared to enhance the ability of FSH to stimulate inhibin secretion. Testosterone had no effect on inhibin production alone or in combination with other regulatory agents. PModS was found to stimulate inhibin secretion approximately 3-fold, but with a delayed time course of stimulation which did not occur until days 5-7 of Sertoli cell culture. Treatment with a combination of PModS and FSH resulted in an apparent maximal stimulation of inhibin secretion. Both forms of PModS, PModS (A) and PModS (B), were found to have equivalent biological activities in their ability to stimulate inhibin production with an apparent half-maximal effective concentration between 10 and 15 ng/ml. The current study provides evidence for the local testicular control of inhibin production and adds to the complexity of the endocrine control of inhibin expression. The cellular interaction is proposed in which LH acts on Leydig cells to stimulate androgen production which in turn acts on peritubular cells to regulate PModS production which subsequently can act on Sertoli cells to control inhibin production. Testicular control of inhibin production provides a potential short feedback loop for the local regulation of androgen production and an additional regulatory element for the pituitary-gonadal axis.
Mol Cell Endocrinol 1989 Oct
PMID:Stimulation of Sertoli cell inhibin secretion by the testicular paracrine factor PModS. 251 83

The effect of insulin and its interaction with intracellular messenger systems on in vitro inhibin production by adult rat isolated seminiferous tubules has been investigated using a recently developed inhibin radioimmunoassay (RIA). Seminiferous tubule segments (5 cm) from intact adult rats were exposed to insulin (0.05-5000 ng/ml) for 2 days of culture. Insulin caused a dose-dependent inhibition of basal inhibin secretion with reversal of this inhibition at very high doses (5000 ng/ml). The ability of follicle-stimulating hormone (FSH) to induce inhibin secretion was also inhibited by insulin (50 ng/ml). Insulin reduced the stimulation of inhibin production by dibutyryl cyclic AMP (dbcAMP) and this effect was prevented by the addition of theophylline (0.4 mM), while theophylline alone was unable to prevent the effect of insulin on basal inhibin secretion. Phorbol 12-myristate 13-acetate (PMA) mimicked the effect of insulin reducing basal and FSH-induced secretion of inhibin. No additive effects on basal inhibin secretion were observed with a combination of PMA and insulin. Ethylenediaminetetraacetic acid (EDTA, 2 mM) significantly reduced basal and FSH-induced inhibin production, while the combined effects of EDTA and insulin on basal and FSH-induced inhibin production were additive. These data demonstrate an inhibitory effect of insulin on inhibin production by isolated seminiferous tubules mediated via at least two mechanisms namely the inhibition of the cAMP-protein kinase A system and stimulation of protein kinase C activity.
Mol Cell Endocrinol 1989 Feb
PMID:The effect of insulin on inhibin production in isolated seminiferous tubule segments from adult rats cultured in vitro. 253 42

Insulin and insulin-like growth factor (IGF)-I inhibit intracellular protein degradation in a variety of different cell types. In the present studies, the IGF-I-induced inhibition of protein metabolism in Chinese hamster ovary (CHO) cells was found to be blocked by polyclonal antibodies to the IGF-II/mannose-6-phosphate phosphate (Man-6-P) receptor, but not by control immunoglobulin. In contrast, these antibodies had no effect on the ability of IGF-I to stimulate glucose uptake in the same cells. The antibodies to the IGF-II/Man-6-P receptor also inhibited the effect of IGF-I and insulin on protein catabolism in human foreskin fibroblasts and human hepatoma cells, respectively. Moreover, CHO cells overexpressing a cDNA coding for the IGF-II/Man-6-P receptor were found to exhibit an increased effect of insulin on protein catabolism. In contrast, the insulin stimulation of glucose uptake is the same in these transfected cells as in the parental CHO cells. These results implicate the IGF-II/Man-6-P receptor in the insulin- and IGF-I-induced inhibition of protein catabolism.
Mol Endocrinol 1989 Jun
PMID:A role for the insulin-like growth factor II/mannose-6-phosphate receptor in the insulin-induced inhibition of protein catabolism. 254 2

Using the well differentiated rat hepatoma Fao we have studied the regulation of phosphoenolpyruvate carboxykinase (PEPCK) mRNA by insulin and glucose and compared these results to glucose production as estimated by glucose release into the medium. Fao cells possess an active gluconeogenic pathway and, when grown in glucose-free medium, release glucose for over 8 h. Addition of the cAMP analog, 8-(4-chlorophenyl-thio) cAMP (8-CTP-cAMP) or increasing the concentration of dihydroxyacetone and oxaloacetate results in an increase in glucose release which can be suppressed by insulin at concentrations between 1 and 100 nM. These effect of cAMP and insulin are associated with parallel changes in the level of mRNAPEPCK. Insulin treatment reduces mRNAPEPCK levels in these cells by 80%; this effect is transient reaching a maximum at 2-4 h. Addition of glucose to cells grown in glucose-free (G-) medium produces a decrease in mRNAPEPCK which is similar in magnitude and kinetics to that produced by insulin. Conversely, when cells grown in normal medium are placed in G- medium mRNAPEPCK levels triple over a period of 8 h, then return toward the basal value. Cells grown in G- medium or in G- medium plus 10nM insulin for 1 yr exhibit only slightly increased levels of mRNAPEPCK and respond to both 8-CTP-cAMP, and insulin, although the response to 8-CTP-cAMP is slightly blunted. These data indicate that glucose and insulin can play independent roles in regulation of PEPCK gene expression, and that these regulatory effects are usually transient.
Mol Endocrinol 1989 May
PMID:Acute and chronic regulation of phosphoenolpyruvate carboxykinase mRNA by insulin and glucose. 254 57

Insulin-like growth factors (IGFs) are expressed by, and are biologically active on, human fetal cells. The mitogenic actions of IGF-I are modulated by the 21-41 kDa class of IGF-binding proteins (IGF-BPs). Using a rabbit anti-human IGF-BP antibody raised against a highly pure 26 kDa IGF-BP derived from amniotic fluid, we have compared the cellular location of IGF-BP and IGF peptides in tissue sections from prostaglandin-induced human abortuses of 14-16 weeks of gestation. The monoclonal and polyclonal antibodies used were raised against human IGF-I, but did not distinguish between IGF-I and IGF-II. Positive staining for IGF-BP was seen in every tissue except brain, spleen and thyroid. With the exception of skin, the cellular distribution of IGF-BP was similar to that of IGF peptides. Strong immunostaining was found in hepatocytes, hepatic erythropoietic cells, pulmonary epithelium, the tubular epithelium of kidney, intestinal epithelia, the fetal adrenal cortex and cardiac and skeletal muscle fibres. In skin, IGF-BP was located throughout the dermis and in the germinal layer of the epidermis. IGF peptide in skin was restricted to the deeper dermal layers. In the tibial epiphyseal growth plate both IGF-BP and IGF peptide were located in chondrocytes throughout the proliferation and hypertrophic zones. The similarity in distribution of IGF-BP and IGF peptides in fetal tissues suggests that the latter may exist predominantly complexed to IGF-BP in or on the surfaces of cells in vivo. The distribution of IGF-BP may define the sites of biological action of IGF peptides.
J Mol Endocrinol 1989 Jan
PMID:Immunological distribution of one form of insulin-like growth factor (IGF)-binding protein and IGF peptides in human fetal tissues. 254 22

In organ culture of pregnant rabbit mammary gland, a low casein synthesis occurs with prolactin (PRL) alone. Insulin markedly potentiates the effect of PRL. Only pharmacological concentrations of insulin (5 micrograms/ml) exert the maximal enhancement, suggesting a possible interaction with the insulin-like growth factor 1 (IGF1) receptor. The presence of IGF1 and insulin binding sites was analyzed and the biological effects of both peptides were compared. Binding of iodinated human IGF1 or porcine insulin to mammary microsomes prepared from mid-pregnant rabbits revealed distinct high affinity binding sites for both peptides (Kd approximately 2 nM). In rabbit mammary explants, we confirmed that only non-physiological concentrations of insulin (greater than or equal to 100 ng/ml) exerted a significant stimulation of the PRL effect. Surprisingly, IGF1 was not found to be more potent than insulin on a molar basis, which did not provide evidence for the exclusive involvement of the IGF1 receptor. Near-physiological concentrations of IGF1 (approximately 100 ng/ml), however, exerted a significant enhancement which suggested a possible action for IGF1 on PRL-induced lactogenesis in vivo.
Mol Cell Endocrinol 1989 Aug
PMID:Comparison of insulin-like growth factor 1 and insulin effects on prolactin-induced lactogenesis in the rabbit mammary gland in vitro. 255 Feb 95

Insulin and the insulin-like growth factors (I and II) are homologous peptides essential to normal metabolism as well as growth. These peptide hormones are present in the brain, and, based on biosynthetic labeling studies as well as evidence for local gene expression, they are synthesized by nervous tissue as well as being taken up by the brain from the peripheral circulation. Furthermore, the presence of insulin and IGF receptors in the brain, on both neuronal and glial cells, also suggests a role for these peptides in the nervous system. Thus, these ligands affect brain electrical activity, either as neurotransmitters or as neuromodulators, altering the release and re-uptake of other neurotransmitters. The insulin and IGF-I and -II receptors found in the brain exhibit a lower molecular weight than corresponding receptors on peripheral tissues, primarily caused by alterations in glycosylation. Despite these alterations, both brain insulin and IGF-I receptors exhibit tyrosine kinase activity in cell-free systems, as do their peripheral counterparts. Brain insulin and IGF-I receptors are developmentally regulated, with the highest levels appearing in fetal or perinatal life. However, the altered glycosylation of brain receptors does not appear until late in fetal development. The receptors are widely distributed in the brain, but especially enriched in the circumventricular organs, choroid plexus, hypothalamus, cerebellum, and olfactory bulb. These studies on the insulin and IGF receptor in brain, add strong support to the suggestion that insulin and IGFs are important neuroactive substances, regulating growth, development, and metabolism in the brain.
Mol Neurobiol
PMID:Insulin and insulin-like growth factor receptors in the nervous system. 255 69

The present study shows that pretreatment of BAC cells with insulin or insulin-like growth factor-I (IGF-I) enhances the cAMP response to maximal concentrations of ACTH and cholera toxin. However, the effects of IGF-I at a nanomolar concentration (50 ng/ml) were higher than for insulin at the same concentration but similar for insulin at a micromolar concentration (10 micrograms/ml). We have investigated whether the effects of the two peptides can be related to some modifications of the guanine nucleotide regulatory binding protein Gs. Insulin enhanced Gs as observed by ADP ribosylation and immunoblotting but the effects were approximately the same at nanomolar and micromolar concentrations; again, the effects of IGF-I (50 ng/ml) were higher. These results indicate that both IGF-I and insulin increase the Gs complex of adenylate cyclase, but IGF-I is more potent than insulin at physiological concentrations.
Mol Cell Endocrinol 1989 Sep
PMID:Insulin-like growth factor-I and insulin increase the stimulatory guanine nucleotide binding protein (Gs) in cultured bovine adrenal cells. 255 33

Insulin-like growth factor-II (IGF-II) is a potent mitogen for several types of cultured cells and tissues. We have studied the interaction of IGF-II with a panel of cultured human breast cancer cell lines, examining the possibility that these cells synthesize and secrete IGF-II activity which could have autocrine/paracrine functions. Synthetic IGF-II was mitogenic in five of seven cell lines tested, including the estrogen receptor-positive lines MCF-7L, ZR75-1, and T47D and the estrogen receptor (ER)-negative lines Hs578T and MDA-231. IGF-II was slightly less potent than IGF-I in stimulating DNA synthesis in MCF-71 cells, an effect that paralleled its ability to compete for [125I]IGF-I binding in these cells. Affinity labeling studies revealed that IGF-II could also compete for binding to the 130,000 mol wt alpha-subunit of the IGF-I receptor. A monoclonal antibody to the IGF-I receptor inhibited the mitogenic effects of IGF-II in MCF-7L and MDA-231 cells, suggesting that this receptor mediates the growth effects of IGF-II in these breast cancer cells. Using a RIA and a RRA, IGF-II-like activity was detected in conditioned medium extracts processed to remove IGF-binding proteins from several breast cancer cell lines, with the highest levels found in conditioned medium from MCF-7L and T47D cell lines. IGF-II mRNA transcripts in MCF-7L and T47D cells were identified by Northern blot analysis and were confirmed by RNase protection assay. IGF-II mRNA was increased by estrogen in MCF-7L cells.(ABSTRACT TRUNCATED AT 250 WORDS)
Mol Endocrinol 1989 Nov
PMID:Insulin-like growth factor-II (IGF-II): a potential autocrine/paracrine growth factor for human breast cancer acting via the IGF-I receptor. 255 2


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