Insulin Receptor Substrate 3 (IRS-3) and IRS-4 Impair IRS-1- and IRS-2-Mediated Signaling

Tsuruzoe, Kaku; Emkey, Renee; Kriauciunas, Kristina M.; Ueki, Kohjiro; Kahn, C. Ronald

doi:10.1128/mcb.21.1.26-38.2001

Cited by 89 publications

(66 citation statements)

References 54 publications

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“…Ad5E1A and IRS proteins NJ Shimwell et al transformed lines that express IRS-4. Such a reciprocal relationship between IRS-1 and IRS-4 has been reported previously (Tsuruzoe et al, 2001). Experiments to determine the half-life of IRS-4 in the presence or absence of E1A showed that E1A expression did not have an effect (data not shown).…”

Section: Regulation Of Irs-4 Expressionsupporting

confidence: 84%

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

et al. 2008

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Using mass spectrometric analysis insulin receptor substrate 4 (IRS-4) has been identified as a novel adenovirus 5 early region 1A (Ad5E1A)-binding protein. IRS-4 interacts with both the transcriptional activation domain (conserved region 3) and the N-terminal region of Ad5E1A13S. Prolonged expression of Ad5E1A13S is required for the observed dramatic increase in the levels of IRS-4 mRNA and protein in Ad5E1-transformed human cell lines. Once expressed, as well as binding to E1A and the insulin receptor, IRS-4 remains tyrosine phosphorylated and constitutively associates with the regulatory p85 subunit of phosphoinositide 3 kinase, resulting in the phosphorylation of Akt (causing activation) and GSK-3b (causing inhibition). Reducing IRS-4 expression using small interfering RNA (siRNA) in established Ad5E1A-expressing cell lines decreases the activation of Akt and cellular proliferation. During Ad5 infection, IRS-4 is not expressed. However, Ad5E1A associates with IRS-1, increasing Akt and GSK-3b phosphorylation and tyrosine phosphorylation of IRS-1 itself. We conclude that the association and altered regulation of IRS proteins by Ad5E1A contribute to the adenovirus-transformed phenotype and modulates viral infection in an Akt-dependent manner.

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Section: Regulation Of Irs-4 Expressionsupporting

confidence: 84%

Adenovirus 5 E1A is responsible for increased expression of insulin receptor substrate 4 in established adenovirus 5-transformed cell lines and interacts with IRS components activating the PI3 kinase/Akt signalling pathway

et al. 2008

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“…A similar increase in PTEN promoter activity was also observed in NIH3T3 cells (data not shown). The IGF axis is able to induce the transcription factor egr-1 in embryonic and cardiac fibroblasts (31,32), and we have recently shown that egr-1 directly activates PTEN during irradiation-induced signaling to a similar magnitude as observed above (12). Therefore, we investigated the requirement of egr-1 for IGF-II regulation of PTEN transcription.…”

Section: Igf-ii Effect Is Epithelial Cell Autonomous-bothmentioning

confidence: 94%

“…It induces IGF-II promoter expression in HepG2 cells in response to hypoxia (36). Also, stimulation of IGF signaling induces egr-1 expression, an effect that may be dependent on IRS-1 (31,32). Thus, egr-1 is both upstream and downstream of IGF-II signaling.…”

Section: Igf-ii Effect Is Epithelial Cell Autonomous-bothmentioning

confidence: 99%

Insulin-like Growth Factor-II Regulates PTEN Expression in the Mammary Gland

Moorehead

Hojilla

Belle

et al. 2003

Journal of Biological Chemistry

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The tumor suppressor PTEN is altered in many cancers, including breast cancer, but only a handful of factors are known to control its expression. PTEN plays a vital role in cell survival and proliferation by regulating Akt phosphorylation, a key component of the phosphatidylinositol 3 kinase (PI3K) pathway. Here we show that insulin-like growth factor-II (IGF-II), which signals through PI3K, regulates PTEN expression in the mammary gland. IGF-II injection into mouse mammary gland significantly increased PTEN expression. Transgenic IGF-II expression also increased mammary PTEN protein, leading to reductions in Akt phosphorylation, epithelial proliferation, and mammary morphogenesis. IGF-II induced PTEN promoter activity and protein levels and this involved the immediate early gene egr-1. Thus, we have identified a novel negative feedback loop within the PI3K pathway where IGF-II induces PTEN expression to modulate its physiologic effects.PTEN 1 is emerging as the most frequently altered tumor suppressor gene other than p53 (1). PTEN is mutated in Cowden's syndrome, a condition of familial cancer predisposition, and is frequently altered in a variety of spontaneous cancers including breast cancers (2-4). The loss of even one PTEN allele in mice leads to a high incidence of tumors in a variety of tissues (3,5). Breast cancer in humans is associated with a loss of heterozygosity or mutation of the PTEN gene, and decreased PTEN expression has been associated with invasive breast cancer and poor prognosis (2, 6, 7). The principal activity of PTEN is to dephosphorylate a phospholipid second messenger, phosphatidylinositol 3,4,5-triphosphate (PIP3), produced by phosphatidylinositol 3 kinase (PI3K) (8, 9). PIP3 is the major activator of the cell survival kinase Akt (8, 9). Thus, negative regulation of the PI3K pathway by PTEN is critical, and the loss of PTEN function creates an environment conducive to tumorigenesis.Despite the obvious importance of PTEN, only a handful of molecules are known to control its expression. Intracellular molecules reported to regulate PTEN transcription include p53 (10), peroxisome proliferator-activated receptor ␥ (11) and Egr-1 (12). These proteins induce PTEN promoter activity and putative binding sites for each have been identified in the PTEN promoter. Transforming growth factor ␤ and progesterone have also been proposed to alter PTEN expression. Transforming growth factor ␤ inhibited PTEN expression, but the nature of this regulation is unknown (13). Endometrial PTEN levels were higher during the secretory compared with the proliferative phase of the menstrual cycle implying an association with progesterone levels (14). Given the critical role of PTEN in the control of cell survival and proliferation, it stands to reason that extracellular factors such as hormones or growth factors should also influence PTEN expression.Insulin-like growth factors (IGFs) are potent mitogens that impact development, are implicated as risk factors in breast cancer, and are overexpressed in human cancers (...

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“…Taken together, these animal studies document that the IRS family proteins have quite distinct biological roles and functional redundancy does not appear to be a major issue in this protein family. A recent study even suggests that the IRS-3 and IRS-4 proteins can impair rather than complement the signalling of their relatives IRS-1 and -2 (Tsuruzoe et al, 2001).…”

Section: Irs Proteinsmentioning

confidence: 99%