Insulin Receptor Substrate 2-mediated Phosphatidylinositol 3-kinase Signaling Selectively Inhibits Glycogen Synthase Kinase 3β to Regulate Aerobic Glycolysis

Landis, Justine M.; Shaw, Leslie M.

doi:10.1074/jbc.m114.564070

Cited by 45 publications

(48 citation statements)

References 58 publications

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“…Label-free mass spectrometric analysis of these immunocomplexes identified 20 proteins that were enriched upon PI3Kbi treatment (Supplementary Table S2). Among these, only the adaptor protein insulin receptor substrate 2 (IRS2) that mediates the activation of signaling pathways in response to ligand stimulation of cell surface receptors is reported to be Tyr-phosphorylated and harbors 6 YXXM motifs, therefore being a potent activator of PI3K (16,19). Subsequent, direct coimmunoprecipitation assays confirmed that PI3Kb inhibition induced a robust p85/IRS2 interaction (Fig.…”

Section: /Brafmentioning

confidence: 86%

Maximizing the Efficacy of MAPK-Targeted Treatment inPTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition

et al. 2016

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The introduction of MAPK pathway inhibitors paved the road for significant advancements in the treatment of BRAF-mutant (BRAFMUT) melanoma. However, even BRAF/MEK inhibitor combination therapy has failed to offer a curative treatment option, most likely because these pathways constitute a codependent signaling network. Concomitant PTEN loss of function (PTENLOF) occurs in approximately 40% of BRAFMUT melanomas. In this study, we sought to identify the nodes of the PTEN/PI3K pathway that would be amenable to combined therapy with MAPK pathway inhibitors for the treatment of PTENLOF/BRAFMUT melanoma. Large-scale compound sensitivity profiling revealed that PTENLOF melanoma cell lines were sensitive to PI3Kβ inhibitors, albeit only partially. An unbiased shRNA screen (7,500 genes and 20 shRNAs/genes) across 11 cell lines in the presence of a PI3Kβ inhibitor identified an adaptive response involving the IGF1R–PI3Kα axis. Combined inhibition of the MAPK pathway, PI3Kβ, and PI3Kα or insulin-like growth factor receptor 1 (IGF1R) synergistically sustained pathway blockade, induced apoptosis, and inhibited tumor growth in PTENLOF/BRAFMUT melanoma models. Notably, combined treatment with the IGF1R inhibitor, but not the PI3Kα inhibitor, failed to elevate glucose or insulin signaling. Taken together, our findings provide a strong rationale for testing combinations of panPI3K, PI3Kβ + IGF1R, and MAPK pathway inhibitors in PTENLOF/BRAFMUT melanoma patients to achieve maximal response. Cancer Res; 76(2); 390–402. ©2015 AACR.

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Section: /Brafmentioning

confidence: 86%

Maximizing the Efficacy of MAPK-Targeted Treatment inPTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition

et al. 2016

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“…SUM-159 cells were a gift from Arthur Mercurio (University of Massachusetts Medical School) and were grown in F12 media (Gibco) containing 5% FBS (MilliporeSigma), 5 μg/ml insulin (MilliporeSigma), and 1 μg/ml hydrocortisone (MilliporeSigma). Mammary tumor cells were isolated from female FVB MMTV-PyMT:Irs1 fl/fl ,Irs2 fl/fl mice, and PyMT:Irs1 -/-,Irs2 -/-cells were generated by infection with adenoviral Cre recombinase as described previously (19). PyMT mouse mammary tumor cells were grown in low-glucose (1 g/l) DMEM (Corning) containing 10% FBS.…”

Section: Methodsmentioning

confidence: 99%

“…Tumor cell functions that are regulated by IRS2 include glucose uptake, migration, and invasion (16). We initially investigated the effect of IRS2 mutations on invasion because PILC tumors have a high incidence of lymphovascular invasion and lymph node metastasis (1) -/-mouse mammary tumor cells ( Figure 4G) (19). Both of these cell lines are dependent upon IRS2 for invasion and their lack of IRS2 expression permits analysis of the IRS2 mutations without a background of endogenous expression.…”

Section: Identification Of Recurrently Mutated Genes In Pilc Pilc Tumentioning

confidence: 99%

IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma

Zhu

Ward²,

et al. 2018

JCI Insight

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“…Taxol, a taxane drug commonly used in cancer treatment, stabilizes microtubules, whereas nocodazole causes depolymerization of the tubulin cytoskeleton (23)(24)(25). IRS signaling was measured by assessing the phosphorylation status of AKT, a downstream signaling effector of PI3K, because the IRS proteins are required for the recruitment and activation of PI3K by the IGF-1R (4,5,26). Although microtubule stabilization by Taxol treatment did not alter the level of AKT activation (Fig.…”

Section: Igf-1r Signaling Is Dependent On the Microtubule Cytoskeletonmentioning

confidence: 99%

“…Notably, the IRS proteins are required for the activation of PI3K downstream of the IR and IGF-1R, which activate AKT and mechanistic target of rapamycin (mTOR) to promote proliferation, survival, motility, protein synthesis, and glucose metabolism (2)(3)(4)(5). IRS-1 and IRS-2 are expressed ubiquitously in humans, including in the normal and malignant mammary epithelium (1).…”

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confidence: 99%

Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells

Mercado-Matos

Clark

Piper

et al. 2017

Journal of Biological Chemistry

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The insulin receptor substrate (IRS) proteins serve as essential signaling intermediates for the activation of PI3K by both the insulin-like growth factor 1 receptor (IGF-1R) and its close family member, the insulin receptor (IR). Although IRS-1 and IRS-2 share significant homology, they regulate distinct cellular responses downstream of these receptors and play divergent roles in breast cancer. To investigate the mechanism by which signaling through IRS-1 and IRS-2 results in differential outcomes, we assessed the involvement of the microtubule cytoskeleton in IRS-dependent signaling. Treatment with drugs that either stabilize or disrupt microtubules reveal that an intact microtubule cytoskeleton contributes to IRS-2-but not IRS-1-mediated activation of AKT by IGF-1. Proximal IGF-1R signaling events, including IRS tyrosine phosphorylation and recruitment of PI3K, are not inhibited by microtubule disruption, indicating that IRS-2 requires the microtubule cytoskeleton at the level of downstream effector activation. IRS-2 colocalization with tubulin is enhanced upon Taxol-mediated microtubule stabilization, which, together with the signaling data, suggests that the microtubule cytoskeleton may facilitate access of IRS-2 to downstream effectors such as AKT. Of clinical relevance is that our data reveal that expression of IRS-2 sensitizes breast carcinoma cells to apoptosis in response to treatment with microtubule-disrupting drugs, identifying IRS-2 as a potential biomarker for the response of breast cancer patients to Vinca alkaloid drug treatment.Insulin receptor substrate 1 (IRS-1) 2 and IRS-2 are cytoplasmic adaptors for the insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R), and they play a major role in determining the cellular response to stimulation of these receptors (1). Notably, the IRS proteins are required for the activation of PI3K downstream of the IR and IGF-1R, which activate AKT and mechanistic target of rapamycin (mTOR) to promote proliferation, survival, motility, protein synthesis, and glucose metabolism (2-5). IRS-1 and IRS-2 are expressed ubiquitously in humans, including in the normal and malignant mammary epithelium (1). Despite their considerable sequence homology, IRS-1 and IRS-2 play divergent roles in breast cancer. In vitro, studies to assess IGF-1-dependent signaling through the IRS proteins in breast carcinoma cells have revealed that IRS-1 primarily regulates proliferation and survival, whereas IRS-2 regulates motility, invasion, and glycolysis (6 -10). In vivo, overexpression of either IRS-1 or IRS-2 in the mouse mammary gland promotes mammary tumorigenesis (11). However, metastasis is diminished in the absence of Irs-2 expression and increased in the absence of Irs-1 expression (9, 12).Differential localization patterns of IRS-1 and IRS-2 in human breast tumors suggest one explanation for their divergent functions in breast cancer (13). In normal breast tissue, ductal carcinoma in situ, and invasive breast tumors, IRS-1 is primarily localized in the nucleus a...

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Insulin Receptor Substrate 2-mediated Phosphatidylinositol 3-kinase Signaling Selectively Inhibits Glycogen Synthase Kinase 3β to Regulate Aerobic Glycolysis

Cited by 45 publications

References 58 publications

Maximizing the Efficacy of MAPK-Targeted Treatment inPTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition

Maximizing the Efficacy of MAPK-Targeted Treatment inPTENLOF/BRAFMUT Melanoma through PI3K and IGF1R Inhibition

IRS2 mutations linked to invasion in pleomorphic invasive lobular carcinoma

Differential involvement of the microtubule cytoskeleton in insulin receptor substrate 1 (IRS-1) and IRS-2 signaling to AKT determines the response to microtubule disruption in breast carcinoma cells

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