Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs)

Wu, Changjiang; Chen, Zhengjun; Ullrich, Axel; Greene, Mark I.; O’Rourke, Donald M.

doi:10.1038/sj.onc.1203748

Cited by 58 publications

(70 citation statements)

References 64 publications

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“…In cells overexpressing wild type SHPS-1, both insulin-dependent activation of MAPK and BDNF-promoted neuronal survival via the PI3K-Akt pathway (Araki et al, 2000) were enhanced, whereas overexpression of mutant SHPS-1 lacking SHP-2 binding sites inhibited the MAPK activation by LPA . In contrast, overexpression of SIRPa1/SHPS-1 in NIH3T3 cells inhibited DNA synthesis and activation of MAPK by epidermal growth factor (EGF) and insulin or PI3K by EGFR (Kharitonenkov et al, 1997;Wu et al, 2000). Although these results suggest the importance of SHPS-1 in SHP-2-dependent signaling, it is still inconclusive and SHPS-1 signaling seems to yield opposing effects depending on the types of ligands and cells.…”

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confidence: 51%

“…Although various types of stimuli appear to activate the tyrosine phosphorylation of SHPS-1, how receptor signaling links with SHPS-1 signaling is not yet clarified Araki et al, 2000;Takeda et al, 1998;Kharitonenkov et al, 1997;Wu et al, 2000). To address this important question, we investigated the interaction between IL-1 receptor signaling and SHPS-1 in Balb3T3 cells and Balb3T3 overexpressing the ECTM mutant.…”

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confidence: 99%

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A role for SHPS-1/SIRPα1 in IL-1β- and TNFα-dependent signaling

et al. 2002

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We investigated the role of SHPS-1/SIRPa1 in IL-1b-and TNFa-dependent signaling that leads to the activation of Erk 1/2 and Akt. Treatment of Balb3T3 cells with IL-1b or TNFa activated tyrosine phosphorylation of SHPS-1, its association with SHP-2 and the phosphorylation of Erk 1/2 and Akt. PP1, a specific inhibitor for the Src family protein tyrosine kinases, strongly inhibited tyrosine phosphorylation of SHPS-1 and complex formation of SHPS-1 with SHP-2 by IL1b. In addition, PP1 substantially inhibited the IL-2b-and TNFa-dependent activation of Erk 1/2 and Akt. Exogenous expression of either SHPS-1 mutants that lack SHP-2 binding function or a dominant negative mutant of SHP-2 markedly inhibited the activation of Erk 1/2 and Akt by IL-1b, whereas wild type SHPS-1 did not. Moreover, IL-1b-stimulation induced association of SHPS-1 with IL-1RAcP, a second subunit of IL-1 receptor, whereas expression of SHPS-1 mutant that lack SHP-2 binding function clearly blocked the association and tyrosine phosphorylation of endogenous SHPS-1. Taken together, our results strongly suggest that activation of Erk 1/2 and Akt by proinflammatory cytokines requires tyrosine phosphorylation of SHPS-1 and subsequent association of SHPS-1 with SHP-2.

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confidence: 51%

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confidence: 99%

A role for SHPS-1/SIRPα1 in IL-1β- and TNFα-dependent signaling

et al. 2002

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“…These observations, associated with the occurrence of erbB1 gene amplification in highgrade gliomas, suggest that maintenance of elevated erbB1 levels is required for erbB1 and its ligand to exert their full oncogenic effects. As consequences of enhanced expression of erbB1, tumoral epithelial cells and glioma cells exhibit increased survival, resistance to induced-cell death and deregulated proliferation (Wu et al, 2000;Yarden and Sliwkowski, 2001;Chakravarti et al, 2002;Ciardiello and Tortora, 2003;Kari et al, 2003). Our results show that TGFa may achieve similar effects on normal astrocytes, without the help of enhanced receptors levels.…”

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confidence: 99%

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

et al. 2006

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Astrocyte death has been implicated in several neuropathological diseases, but the identification of molecules susceptible of promoting astrocyte survival has been elusive. We investigated whether transforming growth factor alpha (TGFa), an erbB1/EGFR ligand, which promotes glioma progression and affects astrocyte metabolism at embryonic and adult stages, regulates astrocyte survival. Primary serum-free astrocyte cultures from postnatal mouse and fetal human cortices were used. Transforming growth factor alpha protected both species of astrocytes from staurosporine-induced apoptosis. In serum-free medium, mouse astrocytes did not survive beyond 2 months while TGFa-treated astrocytes survived up to 12 months. Transforming growth factor alpha also promoted long-term survival of human astrocytes. We additionally extended TGFa proliferative effects to human astrocytes. After 3 days of permanent application, TGFa induced a major downregulation of both erbB1 and erbB2. This downregulation did not impair the functional activation of the receptors, as ascertained by their tyrosine phosphorylation and the continuous stimulation of both ERK/MAPK and PI3K/Akt pathways up to 7 days, the longest time examined. The full cellular effects of TGFa required activation of both transduction pathways. Enhanced proliferation and survival thus define TGFa as a gliatrophin for mammalian astrocytes. These results demonstrate that in normal, non-transformed astrocytes, sustained and functional erbBs activation is achieved without bypassing ligand-induced receptors downregulation.

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“…After treatment with or without the indicated growth factors, cell lysates were prepared as described previously (Wu et al, 2000). Equal amounts of cell lysates, as determined by protein concentration assay with the Dc Protein Assay kit (Bio-Rad, Hercules, CA, USA), were incubated with anti-SHP-2 antibody at 48C for 2 h. Immunocomplexes were collected with Protein A conjugated to Sepharose 4B (Sigma).…”

Section: Immunoprecipitation and Western Blottingmentioning

confidence: 99%

“…Our recent work has implicated that SHP-2 might be involved in regulating phosphatidylinositol 3-kinase (PI3K) signaling; we found that signalregulatory protein (SIRP) regulated EGF-induced PI3K activation through its binding to SHP-2 in human glioblastoma cells. Disruption of SIRP and SHP-2 association by mutation of SIRP eliminated SIRP modulation of PI3K activation (Wu et al, 2000).…”

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The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors

et al. 2001

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SHP-2 is a ubiquitously expressed non-transmembrane tyrosine phosphatase with two SH2 domains. Multiple reverse-genetic studies have indicated that SHP-2 is a required component for organ and animal development. SHP-2 wild-type and homozygous mutant mouse ®bro-blast cells in which the N-terminal SH2 domain was target-deleted were used to examine the function of SHP-2 in regulating Phosphatidylinositol 3-Kinase (PI3K) activation by growth factors. In addition, SHP-2 and various mutants were introduced into human glioblastoma cells as well as SHP-2 7/7 mouse ®bro-blasts. We found that EGF stimulation and EGFR oncoprotein (DEGFR) expression independently induced the co-immunoprecipitation of the p85 subunit of PI3K with SHP-2. Targeted deletion of the N-terminal SH2 domain of SHP-2 severely impaired PDGF-and IGFinduced Akt phosphorylation. Ectopic expression of SHP-2 in U87MG gliobastoma cells elevated EGFinduced Akt phosphorylation, and the e ect was abolished by mutation of its N-terminal SH2 domain. Likewise, the reconstitution of SHP-2 expression in the SHP-2 7/7 cells enhanced Akt phosphorylation induced by EGF while rescuing that induced by PDGF and IGF. Further lipid kinase activity assays con®rmed that SHP-2 modulation of Akt phosphorylation correlated with its regulation of PI3K activation. Based on these results, we conclude that SHP-2 is required for mediating PI3K/Akt activation, and the N-terminal SH2 domain is critically important for a`positive' role of SHP-2 in regulating PI3K pathway activation. Oncogene (2001) 20, 6018 ± 6025.

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Inhibition of EGFR-mediated phosphoinositide-3-OH kinase (PI3-K) signaling and glioblastoma phenotype by Signal-Regulatory Proteins (SIRPs)

Cited by 58 publications

References 64 publications

A role for SHPS-1/SIRPα1 in IL-1β- and TNFα-dependent signaling

A role for SHPS-1/SIRPα1 in IL-1β- and TNFα-dependent signaling

Transforming growth factor alpha acts as a gliatrophin for mouse and human astrocytes

The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors

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