c-SRC Phosphorylates Epidermal Growth Factor Receptor on Tyrosine 845

Sato, Kenichi; Sato, Asomi; Aoto, Mamoru; Fukami, Yasuo

doi:10.1006/bbrc.1995.2574

Cited by 130 publications

(112 citation statements)

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“…Astrocytoma formation induced by expression of v-src in astrocytes was neither increased nor accelerated in p53 +/7 mice (Maddalena et al, 1999). The v-src gene product is able to activate the EGFR signal transduction pathway (Sato et al, 1995). The lack of cooperation in this experiment is in accordance with human data showing that EGFR ampli®cation or overexpression and p53 mutations are mutually exclusive events (Watanabe et al, 1996).…”

Section: Cooperating Genetic Alterationssupporting

confidence: 81%

Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant

Klein

Rüedi

Nozaki³

et al. 2000

Oncogene

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p53-germline mutations located in the core DNA-binding domain have been associated with a more dominant tumor penetrance especially for breast cancer and brain tumors. We previously reported an unusual accumulation of CNS tumors associated with a unique p53 germline mutation, Y236D (deletion of codon 236). To test whether this tissue-speci®c tumor predisposition re¯ects a gain-of-function activity of Y236D, we generated transgenic mice expressing Y236D in astrocytes using the regulatory elements of the glial ®brillary acidic protein (GFAP) gene. After transplacental exposure to N-ethyl-N-nitrosourea (25 mg/kg BW) brain tumors developed in 18% (7/39) of GFAP-Y236D transgenic p53 +/7 mice, while in p53 +/7 mice the incidence was 28% (11/40) (P40.3). However, the mean tumor latency for GFAP-Y236D/p53 +/7 mice was signi®cantly shorter than for p53 +/7 mice, with 19.9 weeks vs 31.6 weeks (P=0.039), respectively. Taken together, cell speci®c expression of Y236D results in an acceleration of tumor progression but does not confer a higher tumor penetrance. Conceivably, the transdominant e ect of Y236D provided a growth advantage early in the progression of neoplastic cells, since the endogenous p53 wild-type allele was lost in all brain tumors independent of the genotype. This re¯ects well observations from human astrocytic neoplasms with p53 mutations. Oncogene (2000) 19, 5329 ± 5337.

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Section: Cooperating Genetic Alterationssupporting

confidence: 81%

Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant

Klein

Rüedi

Nozaki³

et al. 2000

Oncogene

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“…EGFR may be also phosphorylated on tyrosine 845 that is positioned outside the autophosphorylation domain. This site has been shown to be a target for Src kinase (Sato et al, 1995;Tice et al, 1999). As shown in Figure 5E, the phosphorylation of tyrosine 845 was elevated following CDDP treatment in DHER14 cells as well as in glioma cells.…”

Section: A Role For Src-family Kinases In Cddp-induced Egfr Activationmentioning

confidence: 82%

Cisplatin-induced activation of the EGF receptor

2002

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Cisplatin (CDDP) is an efficient DNA-damaging antitumor agent employed for the treatment of various human cancers. CDDP activates nuclear as well as cytoplasmatic signaling pathways involved in regulation of the cell cycle, damage repair and programmed cell death. Here we report that CDDP also activates a membrane-integrated protein, the epidermal growth factor receptor (EGFR). We show that EGFR is activated in response to CDDP in various types of cells that overexpress the receptor, including transformed human glioma cells and human breast tumor cells. CDDP-induced EGFR activation requires its kinase activity, as it can be blocked by an EGFR kinase inhibitor or by expression of a kinase dead receptor. We also show that CDDP-induced EGFR activation is independent of receptor ligand. CDDP induces the activation of c-Src, and EGFR activation is blocked by Src-family inhibitor PP1, suggesting that Src kinases mediate CDDP-induced EGFR activation. We propose that EGFR activation in response to CDDP is a survival response, since inhibition of EGFR activation enhances CDDP-induced death. These findings show that signals generated by DNA damage can modulate EGFR activity, and argue that interfering with CDDP-induced EGFR activation in tumor cells might be a useful approach to sensitize these cells to genotoxic agents.

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“…The corresponding residue in EGFR, Y845, has been found phosphorylated by c-Src in an EGFdependent manner both in vivo and in vitro (Sato et al, 1995). Further examination of the structural features of p185 neu and EGFR kinase domain activation may facilitate the understanding of cross-talking between signaling pathways and the development of site-speci®c inhibitors of erbB receptor catalytic function contributing to oncogenesis.…”

Section: Discussionmentioning

confidence: 99%

Absence of autophosphorylation site Y882 in the p185neu oncogene product correlates with a reduction of transforming potential

et al. 1998

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Autophosphorylation of type I receptor tyrosine kinases (RTKs) comprises one step in the signaling events mediated by erbB receptors such as p185 neu and EGFR. Previous analysis of p185 neu has indicated that there are at least ®ve tyrosine autophosphorylation sites, Y882, Y1028, Y1143, Y1226/7 and Y1253, of which Y882 might be important because of its location in the kinase activity domain. We have speci®cally analysed the e ect of a Y882F (phenylalanine substituted for tyrosine at position 882) mutation in the enzymatic active domain. We also deleted the carboxyl terminal 122 amino acids which contained three other autophosphorylation sites (TAPstop) and combined mutants of that deletion with Y882F (Y882F/APstop). Both in vitro and in vivo transformation assays showed that substitution of tyrosine 882 by phenylalanine signi®cantly decreased the transforming potential of activated, oncogenic p185 neu , although no signi®cant di erence in the total phosphotyrosine levels of the mutant proteins were observed. To analyse mitogenic signaling in response to ligand, the intracellular domains of p185 neu and Y882F were fused with the extracellular domain of the EGF receptor. The proliferation of cells expressing these chimeric receptors was EGF-dependent, and cells expressing EGFR/Y882F chimeric receptors were less responsive to EGF stimulation than those expressing EGFR/neu receptors. In vitro kinase assays demonstrated that abolishing the autophosphorylation site Y882 diminished the enzymatic tyrosine kinase activity of p185 neu . These studies, taken together with the phenotypic inhibition observed with cells expressing Y882F, suggest that the tyrosine 882 residue may be important for p185 neu -mediated transformation by a ecting the enzymatic kinase function of the p185 neu receptor.

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c-SRC Phosphorylates Epidermal Growth Factor Receptor on Tyrosine 845

Cited by 130 publications

References 0 publications

Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant

Reduced latency but no increased brain tumor penetrance in mice with astrocyte specific expression of a human p53 mutant

Cisplatin-induced activation of the EGF receptor

Absence of autophosphorylation site Y882 in the p185neu oncogene product correlates with a reduction of transforming potential

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