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, Jose; Clark, Jennifer L.; Piper, Andrew; Janusis, Jenny; Shaw, Leslie M.

doi:10.1074/jbc.m117.785832

Cited by 21 publications

(14 citation statements)

References 39 publications

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“…. IRS2 has previously been reported to participate in regulation of the PI3K/Akt pathway (28)(29)(30). Therefore, it was hypothesized that miR-766 may target IRS2 to inhibit the activation of PI3K/Akt signaling in PTC cells.…”

Section: Mir-766 Suppresses Activation Of the Pi3k/akt Pathway In Ptcmentioning

confidence: 99%

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway

Zhao

Chen

et al. 2018

Int J Oncol

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MicroRNAs (miRNAs/miRs) are widely dysregulated in papillary thyroid cancer (PTC). Dysregulated miRNAs, together with their target genes, comprise a complex network that has been implicated in the regulation of PTC pathogenesis. Further knowledge of the functional roles of aberrantly expressed miRNAs in PTC, and the underlying molecular mechanisms, may assist in the identification of novel therapeutic targets. miR-766 has been well studied in human cancer; however, the expression status, specific roles and regulatory mechanisms of miR-766 in PTC remain unclear. The present study aimed to detect miR-766 expression in PTC tissues and cell lines, to explore the biological roles of miR-766 in the malignant biological behaviors of PTC cells, and to determine the underlying mechanism of action of miR-766 in PTC cells. The results revealed that miR-766 was downregulated in PTC tissues and cell lines, and its downregulation was strongly associated with TNM stage and lymph node metastasis. Overexpression of miR-766 inhibited PTC cell proliferation, colony formation, migration and invasion, promoted cell apoptosis and reduced tumor growth in vivo. Mechanistically, insulin receptor substrate 2 (IRS2) was identified as a direct target of miR-766 in PTC cells. IRS2 was upregulated in PTC tissues, and this was inversely correlated with miR-766 expression. Inhibition of IRS2 simulated the tumor suppressor activity of miR-766 in PTC cells. Restoration of IRS2 expression negated the tumor-suppressing effects of miR-766 overexpression on PTC cells. Notably, miR-766 directly targeted IRS2 to inhibit activation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) pathway in PTC cells in vitro and in vivo. Overall, these findings indicated that miR-766 may inhibit the malignant biological behaviors of PTC cells by directly targeting IRS2 and regulating the PI3K/Akt pathway, thus suggesting that this miRNA may be a promising therapeutic target for PTC.

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Section: Mir-766 Suppresses Activation Of the Pi3k/akt Pathway In Ptcmentioning

confidence: 99%

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway

Zhao

Chen

et al. 2018

Int J Oncol

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“…In breast cancers, IRS-1 and IRS-2 are the two major isoforms that mediate IGF/insulin signaling. The role of IRS-1/2 proteins in breast malignancies has been well documented: IRS-1 promotes tumor growth [3, 4], whereas IRS-2 stimulates motility [3, 5, 6]. …”

Section: Introductionmentioning

confidence: 99%

Insulin Receptor Substrate Suppression by the Tyrphostin NT157 Inhibits Responses to Insulin-Like Growth Factor-I and Insulin in Breast Cancer Cells

et al. 2018

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Insulin and insulin-like growth factor (IGF) signaling systems regulate breast cancer growth, progression, and metastasis. The insulin receptor substrates 1 and 2 (IRS1/2) transduce signaling from the type I IGF receptor (IGF-IR) and insulin receptor (InR) to mediate the biological effects of receptor activation. In breast cancer, IRS-1 plays a critical role in cancer cell proliferation while IRS-2 is associated with motility and metastasis. NT157, a small-molecule tyrphostin, downregulates IRS proteins in several model systems. In breast cancer cells, NT157 treatment suppressed IRS protein expression in a dose-dependent manner. Exposure to NT157 inhibited the activation of downstream signaling mediated by the IRS proteins. NT157 induced a MAPK-dependent serine phosphorylation of IRS proteins which resulted in disassociation between IRS proteins and their receptors resulting in IRS degradation. In estrogen receptor-α-positive (ERα+) breast cancer cells (MCF-7 and T47D), NT157 also resulted in cytoplasmic ERα downregulation likely because of disruption of an IRS-1-IGF-IR/InR/ERα complex. NT157 decreased S phase fraction, monolayer, and anchorage-independent growth after IGF/insulin treatment in ERα+ breast cancer cells. NT157 downregulation of IRS protein expression also sensitized ERα+ breast cancer cells to rapamycin. Moreover, NT157 inhibited the growth of tamoxifen-resistant ERα+ breast cancer cells. Given that both IGF-IR and InR play a role in cancer biology, targeting of IRS adaptor proteins may be a more effective strategy to inhibit the function of these receptors.

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“…Alternatively, interactions with the region could modify the downstream outcomes of PI3K signaling to elicit divergent outcomes. In this regard, the differential requirement for an intact microtubule cytoskeleton in the IRS-dependent activation of AKT suggests that one mechanism by which interactions with the INV region could alter PI3K signaling outcomes is through the regulation of IRS2 trafficking that localizes PI3K signaling to intracellular locations necessary for regulating invasion (48). This could impact access to distinct pools of PI3K downstream effectors that promote invasion.…”

Section: Discussionmentioning

confidence: 99%

Identification of a Novel Invasion-Promoting Region in Insulin Receptor Substrate 2

Mercado-Matos

Janusis

Zhu

et al. 2018

Molecular and Cellular Biology

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Although the insulin receptor substrate (IRS) proteins IRS1 and IRS2 share considerable homology and activate common signaling pathways, their contributions to breast cancer are distinct. IRS1 has been implicated in the proliferation and survival of breast tumor cells. In contrast, IRS2 facilitates glycolysis, invasion, and metastasis. To determine the mechanistic basis for IRS2-dependent functions, we investigated unique structural features of IRS2 that are required for invasion. Our studies revealed that the ability of IRS2 to promote invasion is dependent upon upstream insulin-like growth factor 1 receptor (IGF-1R)/insulin receptor (IR) activation and the recruitment and activation of phosphatidylinositol 3-kinase (PI3K), functions shared with IRS1. In addition, a 174-amino-acid region in the IRS2 C-terminal tail, which is not conserved in IRS1, is also required for IRS2-mediated invasion. Importantly, this "invasion (INV) region" is sufficient to confer invasion-promoting ability when swapped into IRS1. However, the INV region is not required for the IRS2-dependent regulation of glucose uptake. Bone morphogenetic protein 2-inducible kinase (BMP2K) binds to the INV region and contributes to IRS2-dependent invasion. Taken together, our data advance the mechanistic understanding of how IRS2 regulates invasion and reveal that IRS2 functions important for cancer can be independently targeted without interfering with the metabolic activities of this adaptor protein.

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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

Cited by 21 publications

References 39 publications

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway

MicroRNA‑766 inhibits papillary thyroid cancer progression by directly targeting insulin receptor substrate 2 and regulating the PI3K/Akt pathway

Insulin Receptor Substrate Suppression by the Tyrphostin NT157 Inhibits Responses to Insulin-Like Growth Factor-I and Insulin in Breast Cancer Cells

Identification of a Novel Invasion-Promoting Region in Insulin Receptor Substrate 2

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