Depletion of insulin receptor substrate 2 reverses oncogenic transformation induced by v-src

Sun, Hongzhi; Xu, Lin; Zhou, Bo; Zang, Wei-Jin; Wu, Shufang

doi:10.1038/aps.2011.18

Cited by 3 publications

(4 citation statements)

References 25 publications

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“…Most of these studies suggest that Src function is required in the upstream part of the signaling pathway - in some contexts, Src associates with and/or is activated by the ligand-bound receptor 8 9 10 11 12 . Intersections of Src signaling with the insulin/IGF pathway have also been described at the level of insulin receptor substrate (IRS) proteins 13 14 , phosphoinositide 3-kinase (PI3K) 15 and in the activation of AKT 16 17 18 19 . The main limitation of these biochemical studies is that they are mostly based on experiments in cell culture and often employ tools like the rather unspecific Src inhibitors PP1 and PP2, and therefore it is difficult to deduce the relevance of Src signaling in actual in vivo conditions in the living organism from them.…”

mentioning

confidence: 99%

Src tyrosine kinase signaling antagonizes nuclear localization of FOXO and inhibits its transcription factor activity

Bülow

Hoch

et al. 2014

Sci Rep

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Biochemical experiments in mammalian cells have linked Src family kinase activity to the insulin signaling pathway. To explore the physiological link between Src and a central insulin pathway effector, we investigated the effect of different Src signaling levels on the Drosophila transcription factor dFOXO in vivo. Ectopic activation of Src42A in the starved larval fatbody was sufficient to drive dFOXO out of the nucleus. When Src signaling levels were lowered by means of loss-of-function mutations or pharmacological inhibition, dFOXO localization was shifted to the nucleus in growing animals, and transcription of the dFOXO target genes d4E-BP and dInR was induced. dFOXO loss-of-function mutations rescued the induction of dFOXO target gene expression and the body size reduction of Src42A mutant larvae, establishing dFOXO as a critical downstream effector of Src signaling. Furthermore, we provide evidence that the regulation of FOXO transcription factors by Src is evolutionarily conserved in mammalian cells.

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confidence: 99%

Src tyrosine kinase signaling antagonizes nuclear localization of FOXO and inhibits its transcription factor activity

Bülow

Hoch

et al. 2014

Sci Rep

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“…The Stat3 signaling pathway has been shown to interact with the PI3K-AKT-mTOR, MAPK, and p38 pathways 20 , 42 , 43 , 44 , 45 , 46 ( Figure 4a ). Therefore, we examined the effects of tanshinone-1 on the key signaling molecules, AKT, ERK, and p38, of these pathways.…”

Section: Resultsmentioning

confidence: 99%

Tanshinone-1 induces tumor cell killing, enhanced by inhibition of secondary activation of signaling networks

et al. 2013

Cell Death Dis

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Tumor multidrug resistance (MDR) can result from overexpression of drug transporters and deregulation of cellular signaling transduction. New agents and strategies are required for overcoming MDR. Here, we report that tanshinone-1, a bioactive ingredient in traditional Chinese medicine, directly killed MDR tumor cells and their corresponding parental cells, which was potentiated by inhibition of secondary activation of signaling networks. Tanshinone-1 was slightly more potent at inducing cytotoxicity and apoptosis in MDR cells than in corresponding parental cells. Tanshinone-1-induced MDR cell killing was independent of the function and expression of drug transporters but was partially correlated with the phosphatase-dependent reduction of phospho-705-Stat3, which secondarily activated p38-, AKT-, and ERK-involved signaling networks. Cotreatments with p38, AKT, and ERK inhibitors potentiated the anti-MDR effects of tanshinone-1. Our study presents a model for MDR cell killing using a compound of natural origin. This model could lead to new therapeutic strategies for targeting signaling network(s) in MDR cancers as well as new strategies for multitarget design.

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“…Overexpression or activation of Src is frequently detected in a variety of tumors [17,19]. It has been reported that IRS2 depletion can reverse oncogenic transformation induced by Src [22], suggesting that IRS2 is a key effector downstream of Src. Our work reveals that AFB1 can induce Src phosphorylation and stabilize IRS2.…”

Section: Discussionmentioning

confidence: 99%

“…Under hypoxic conditions, Src activation leads to overexpression of vascular endothelial growth factor (VEGF), matrix metalloproteinases (MMP), and interleukin-8, which in turn stimulate tumor angiogenesis and metastasis [14,19,20]. Src interacts with both IRS1 and IRS2, which have critical roles in cell growth, migration, and metabolism [21,22]. IRS1/2 relay signaling through insulin receptor and IGF-1R by recruiting many Src homology 2 (SH2) domain-containing proteins [23,24].…”

Section: Introductionmentioning

confidence: 99%

Aflatoxin B1 induces Src phosphorylation and stimulates lung cancer cell migration

et al. 2015

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AflatoxinB1 (AFB1) is well known as a potent carcinogen. Epidemiological studies have shown an association between AFB1 exposure and lung cancer in humans. AFB1 can induce the mutations of genes such as tumor suppressor p53 through its metabolite AFB1-8,9-exo-epoxide, which acts as a mutagen to react with DNA. In addition, recent study demonstrates AFB1 positively regulates type I insulin-like growth factor receptor (IGF-IR) signaling in hepatoma cells. The current study aims to determine the effects of AFB1 on Src kinase and insulin receptor substrate (IRS) in lung cancer cells and the effects of AFB1 on lung cancer cell migration. To this end, the effects of AFB1 on IRS expression, Src, Akt, and ERK phosphorylation were measured by Western blot analysis. The migration of lung cancer cells was detected by wound-healing assay. AFB1 downregulates IRS1 but paradoxically upregulates IRS2 through positive regulation of the stability of IRS2 and the proteasomal degradation of IRS1 in lung cancer cell lines A549 and SPCA-1. In addition, AFB1 induces Src, Akt, and ERK1/2 phosphorylation. Treatment of lung cancer cells with Src inhibitor saracatinib abrogates AFB1-induced IRS2 accumulation. Moreover, AFB1 stimulates lung cancer cell migration, which can be inhibited by saracatinib. We conclude that AFB1 may upregulate IRS2 and stimulate lung cancer cell migration through Src.

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Depletion of insulin receptor substrate 2 reverses oncogenic transformation induced by v-src

Cited by 3 publications

References 25 publications

Src tyrosine kinase signaling antagonizes nuclear localization of FOXO and inhibits its transcription factor activity

Src tyrosine kinase signaling antagonizes nuclear localization of FOXO and inhibits its transcription factor activity

Tanshinone-1 induces tumor cell killing, enhanced by inhibition of secondary activation of signaling networks

Aflatoxin B1 induces Src phosphorylation and stimulates lung cancer cell migration

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