scholarly journals Selective modulation of type 1 insulin-like growth factor receptor signaling and functions by β1 integrins

2004 ◽  
Vol 166 (3) ◽  
pp. 407-418 ◽  
Author(s):  
Hira Lal Goel ◽  
Mara Fornaro ◽  
Loredana Moro ◽  
Natalia Teider ◽  
Johng S. Rhim ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Cell Adhesion ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Downstream Effectors ◽  
Β1 Integrins ◽  
Igf I ◽  
Factor Type

We show here that β1 integrins selectively modulate insulin-like growth factor type I receptor (IGF-IR) signaling in response to IGF stimulation. The β1A integrin forms a complex with the IGF-IR and insulin receptor substrate-1 (IRS-1); this complex does not promote IGF-I mediated cell adhesion to laminin (LN), although it does support IGF-mediated cell proliferation. In contrast, β1C, an integrin cytoplasmic variant, increases cell adhesion to LN in response to IGF-I and its down-regulation by a ribozyme prevents IGF-mediated adhesion to LN. Moreover, β1C completely prevents IGF-mediated cell proliferation and tumor growth by inhibiting IGF-IR auto-phosphorylation in response to IGF-I stimulation. Evidence is provided that the β1 cytodomain plays an important role in mediating β1 integrin association with either IRS-1 or Grb2-associated binder1 (Gab1)/SH2-containing protein-tyrosine phosphate 2 (Shp2), downstream effectors of IGF-IR: specifically, β1A associates with IRS-1 and β1C with Gab1/Shp2. This study unravels a novel mechanism mediated by the integrin cytoplasmic domain that differentially regulates cell adhesion to LN and cell proliferation in response to IGF.

Insulin-like growth factor type-I (IGF-I) modulates the inflammatory response within the liver

2002 ◽  
Vol 36 ◽  
pp. 10
Author(s):  
Sonia Sanz ◽  
Carlos M. Rodriguez-Ortigosa ◽  
Kay Lund ◽  
David A. Brenner ◽  
Jesus Prieto
Keyword(s):  
Growth Factor ◽  
Inflammatory Response ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Factor Type

INSULIN-LIKE GROWTH FACTOR TYPE I AND INSULIN-LIKE GROWTH FACTOR TYPE II STIMULATE OESTRADIOL-17β HYDROXYSTEROID DEHYDROGENASE (REDUCTIVE) ACTIVITY IN BREAST CANCER CELLS

1991 ◽  
Vol 129 (2) ◽  
pp. R5-R8 ◽  
Author(s):  
Anita Singh ◽  
M.J. Reed
Keyword(s):  
Breast Cancer ◽  
Growth Factor ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Hydroxysteroid Dehydrogenase ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
Factor Type ◽  
Mcf 7

ABSTRACT Oestradiol-17β hydroxysteroid dehydrogenase (E2DH) is present in normal and malignant breast tissues and also in cultured breast cancer cells. It can act in a reductive direction to convert oestrone to the biologically active oestrogen, oestradiol, or in an oxidative direction to metabolize oestradiol to oestrone and may therefore have a crucial role in regulating breast tissue concentrations of oestradiol. Insulin-like growth factor-type I (IGF-I) and IGF-II are both mitogens for breast cancer cells. In this study we have examined the effect of these growth factors on the reductive and oxidative activities of E2DH in MCF-7 (receptor positive) and MDA-MB-231 (receptor negative) breast cancer cells. Both IGF-I (80 ng/ml) and IGF-II (80 ng/ml) significantly stimulated E2DH reductive activity (up to 138%) in MCF-7 cells but had no effect on oxidative activity. Addition of IGF-II (100 ng/ml) to MDA-MB-231 cells resulted in a small but statistically significant (p<0.05) increase in E2DH reductive activity (18%) but in these cells reductive activity is 25-70 times lower than oxidative activity. If IGF-I and IGF-II act to stimulate E2DH reductive activity in breast tumours then such a mechanism could account for the increased concentrations of oestradiol detected in breast tumours.

scholarly journals Dual Regulation of MMP-2 Expression by the Type 1 Insulin-like Growth Factor Receptor

2004 ◽  
Vol 279 (19) ◽  
pp. 19683-19690 ◽  
Author(s):  
Donglei Zhang ◽  
Menashe Bar-Eli ◽  
Sylvain Meloche ◽  
Pnina Brodt
Keyword(s):  
Protein Synthesis ◽  
Growth Factor ◽  
Kinase Inhibitors ◽  
Growth Factor Receptor ◽  
Signal Transduction Pathway ◽  
Dominant Negative ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Igf I ◽  
In Cells

The matrix metalloproteinase (MMP)-2 has been recognized as a major mediator of basement membrane degradation, angiogenesis, tumor invasion, and metastasis. The factors that regulate its expression have not, however, been fully elucidated. We previously identified the type I insulin-like growth factor (IGF-I) receptor as a regulator of MMP-2 synthesis. The objective of the present study was to investigate the signal transduction pathway(s) mediating this regulation. We show here that in Lewis lung carcinoma subline H-59 cells treated with IGF-I (10 ng/ml), the PI 3-kinase (phosphatidylinositol 3′-kinase) /protein kinase B (Akt) and C-Raf/ERK pathways were activated, andMMP-2promoter activity, mRNA, and protein synthesis were induced. MMP-2 induction was blocked by the PI 3-kinase inhibitors LY294002 and wortmannin, by overexpression of a dominant-negative Akt or wild-type PTEN (phosphatase and tensin homologue deleted on chromosome 10), and by rapamycin. In contrast, a MEK inhibitor PD98059 failed to reduceMMP-2promoter activation and actually increasedMMP-2mRNA and protein synthesis by up to 30%. Interestingly, suppression of PI 3-kinase signaling by a dominant-negative Akt enhanced ERK activity in cells stimulated with 10 ng/ml but not with 100 ng/ml IGF-I. Furthermore, at the higher (100 ng/ml) IGF-I concentration, C-Raf and ERK, but not PI 3-kinase activation, was enhanced, and this resulted in down-regulation of MMP-2 synthesis. This effect was reversed in cells expressing a dominant-negative ERK mutant. The results suggest that IGF-I can up-regulate MMP-2 synthesis via PI 3-kinase/Akt/mTOR (the mammalian target of rapamycin) signaling while concomitantly transmitting a negative regulatory signal via the Raf/ERK pathway. The outcome of IGF-IR (the receptor for IGF-I) activation may ultimately depend on factors, such as ligand bioavailability, that can shift the balance preferentially toward one pathway or the other.

Insulin-like growth factor-I and type I insulin-like growth factor receptor in 85% O2-exposed rat lung

1996 ◽  
Vol 271 (1) ◽  
pp. L139-L149 ◽  
Author(s):  
R. N. Han ◽  
V. K. Han ◽  
S. Buch ◽  
B. A. Freeman ◽  
M. Post ◽  
...  
Keyword(s):  
Growth Factor ◽  
Growth Factor Receptor ◽  
Airway Hyperreactivity ◽  
Alveolar Epithelial Cells ◽  
Northern Analysis ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Factor I ◽  
Igf I ◽  
Growth Factor I

The expression of insulin-like growth factor I (IGF-I) and insulin-like growth factor II (IGF-II) was studied in the lungs of adult rats exposed to air or 85% O2, using Northern analysis, in situ hybridization, and immunohistochemistry. Distribution of the type I insulin-like growth factor receptor (IGF-IR) was assessed by immunohistochemistry. IGF-I, but not IGF-II, was localized to airway epithelium, while IGF-IR was localized to perivascular and peribronchial cells, in the lungs of animals breathing air. IGF-II mRNA did not increase with exposure to 85% O2, but IGF-II was localized to sites of perivascular edema and to occasional peribronchial cells. A widespread increase in IGF-I mRNA and peptide was seen after both a 6-day and a 14-day exposure to O2, with maximal expression in the airway and alveolar epithelium, and lesser expression in interstitial cells. After 6 days in 85% O2, increased IGF-IR immunoreactivity was localized to both perivascular and peribronchial cells and to endothelial cells. By 14 days in 85% O2, IGF-IR immunoreactivity was also localized to alveolar epithelial cells. The distribution of IGF-IR immunoreactivity was consistent with a paracrine role for IGF-I in O2-mediated pulmonary hypertension and airway hyperreactivity, by mediating smooth muscle cell hyperplasia, as well as a role in endothelial cell repair and late pneumocyte hyperplasia. The relative insensitivity of IGF-IR immunohistochemistry did not allow us to identify cells with low abundance IGF-IR, and potential cellular targets for IGF-I actions after O2-exposure may be even more extensive than those recognized here.

scholarly journals Regulation of Id Gene Expression by Type I Insulin-Like Growth Factor: Roles of STAT3 and the Tyrosine 950 Residue of the Receptor

2001 ◽  
Vol 21 (16) ◽  
pp. 5447-5458 ◽  
Author(s):  
Marco Prisco ◽  
Francesca Peruzzi ◽  
Barbara Belletti ◽  
Renato Baserga
Keyword(s):  
Gene Expression ◽  
Growth Factor ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Dominant Negative ◽  
Dominant Negative Mutant ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Proliferation And Differentiation ◽  
Igf I

ABSTRACT Id proteins are known to play important roles in the proliferation and differentiation of many cell types. The type 1 insulin-like growth factor receptor (IGF-IR), activated by its ligand, induces the differentiation of 32D IGF-IR cells, a murine hematopoietic cell line, expressing a human IGF-IR. Expression in 32D IGF-IR cells of a dominant negative mutant of Stat3 (DNStat3) inhibits IGF-I-mediated differentiation. DNStat3 causes a dramatic increase in Id2 gene expression. This increase, however, is IGF-I dependent and is abrogated by a mutation at tyrosine 950 of the IGF-IR. These results indicate that in 32D cells, the IGF-IR regulates the expression of the Id2 gene and that this regulation is modulated by both positive and negative signals. Our results also suggest that in this model, Id2 proteins influence the differentiation program of cells but are not sufficient for the full stimulation of their proliferation program.

scholarly journals Expression of a type I insulin-like growth factor receptor with low affinity for insulin-like growth factor II

1992 ◽  
Vol 281 (2) ◽  
pp. 413-417 ◽  
Author(s):  
E L Germain-Lee ◽  
M Janicot ◽  
R Lammers ◽  
A Ullrich ◽  
S J Casella
Keyword(s):  
Growth Factor ◽  
Cell Surface ◽  
Growth Factor Receptor ◽  
Cell Surface Receptors ◽  
Type I ◽  
Insulin Like Growth Factor ◽  
Surface Receptors ◽  
3T3 Fibroblasts ◽  
Igf I ◽  
Nih 3T3

We investigated the binding properties of the type I insulin-like growth factor (IGF) receptor expressed in NIH-3T3 fibroblasts transfected with a human type I receptor cDNA. Cell surface receptors bound IGF-I with KD = 1 nM as predicted. Although recent studies have suggested that IGF-I and IGF-II bind to type I receptors with near-equal affinity, the receptors in this system bound IGF-II with much lower affinity (KD = 15-20 nM). When type I receptors from the transfected cells were solubilized and immunopurified, however, both 125I-IGF-I and 125I-IGF-II bound to the purified receptors with extremely high and relatively similar affinities (KD = 8 and 17 pM respectively). Thus the immunopurified receptors had higher affinity but lower specificity for the two ligands. The monoclonal antibody alpha IR-3 effectively inhibited IGF-I binding to cell surface receptors (75 +/- 10%), but did not inhibit IGF-II binding. In the purified receptor assay, alpha IR-3 also inhibited IGF-I binding more effectively than IGF-II binding (38 +/- 7% versus 10 +/- 4%). We conclude that the products of this cDNA can account for the binding patterns that we previously observed in receptors immunopurified from human placenta. The differential effect of alpha IR-3 on IGF-I versus IGF-II raises the possibility that these homologous growth factors bind to immunologically distinct epitopes on the type I receptor.

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