Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase

Elenius, Klaus; Choi, Chan-Bum; Paul, Subroto; Santiestevan, Eric; Nishi, Eiichiro; Klagsbrun, Michael

doi:10.1038/sj.onc.1202612

Cited by 151 publications

(176 citation statements)

References 55 publications

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“…Among the samples, this antibody detected ErbB4 immunoreactive bands at roughly 180 and 80kDa ( Figure 2B), which correspond to full-length ErbB4 and the cleaved ErbB4 intracellular domain, respectively (Elenius et al 1997;Elenius et al 1999;Hahn et al 2006;Plowman et al 1993;Vecchi et al 1996). The ErbB4 antibody also detected several immunoreactive bands ranging from 21-62kDa ( Figure 2B), which have not been described in human brain.…”

Section: Detected Nrg1 and Erbb4 Immunoreactive Bandsmentioning

confidence: 86%

Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Chong

Thompson

Beltaifa

et al. 2008

Schizophrenia Research

170

126

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Neuregulin-1 (NRG1) and its receptor, ErbB4, have been implicated in schizophrenia at both gene and transcript levels. The present investigation compared NRG1 and ErbB4 protein levels in prefrontal cortical (PFC) cytoplasmic and nuclear fractions among normal, schizophrenic, bipolar and major depressed subjects from the Stanley Consortium. We used immunoblotting procedures to examine potential NRG1 and ErbB4 immunoreactive bands, but specifically quantified NRG1 immunoreactive signals at 42, 48 and 53kDa and ErbB4 immunoreactive signals at 21, 55, 60 and 180kDa. PFC cytoplasmic 53kDa NRG1 protein levels were significantly increased (~20%) in schizophrenic patients relative to each of the other subject groups. We also detected a trend towards diagnostic effects on PFC cytoplasmic full-length (180kDa) ErbB4 protein levels, and post hoc tests revealed that these quantities were significantly increased (~30%) in schizophrenic patients relative to normal and to depressed subjects. In addition, we examined the levels of potential ErbB4 cleavage products at 21, 55 and 60kDa relative to those of full-length ErbB4 in the PFC fractions. We detected trends for diagnostic effects on PFC cytoplasmic 21kDa/180kDa and 55kDa/180kDa ratios, and post hoc tests revealed that these ratios were significantly reduced in schizophrenic patients relative to normal individuals. Our investigation suggests that schizophrenia-associated NRG1 and ErbB4 mRNA elevations also occur at the protein level and may be specific to schizophrenia. We hypothesize that ErbB4 proteolytic processing may also be altered in schizophrenia, yielding altered ratios of functionally distinct forms of ErbB4.

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Section: Detected Nrg1 and Erbb4 Immunoreactive Bandsmentioning

confidence: 86%

Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Chong

Thompson

Beltaifa

et al. 2008

Schizophrenia Research

170

126

View full text Add to dashboard Cite

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“…In this regard, ErbB-3 has seven recognition sequences for the p85 regulatory subunit of PI3K (Soltoff et al, 1994). A p85 binding sequence is also contained in a splicing variant of ErbB-4, that is able to activate the PI3K/AKT pathway to a much lesser extent than ErbB-3 (Elenius et al, 1999). In a study by Moasser et al (2001), ErbB-3 expression was indeed found in all but one of the cell lines that are growth inhibited by ZD1839.…”

Section: Mechanism Of Action Of Egfr-tkismentioning

confidence: 99%

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs): Simple drugs with a complex mechanism of action?

Normanno

Maiello

Luca

2002

Journal Cellular Physiology

130

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A range of target-based agents for the treatment of solid tumors are in development. The epidermal growth factor receptor (EGFR) has been identified as a relevant target as it is involved in regulating several cellular functions important in the proliferation and survival of cancer cells, is commonly expressed at high levels in a range of tumors, and high expression is often related to poor prognosis. EGFR is a member of the ErbB family of receptors which also includes ErbB-2, ErbB-3, and ErbB-4. These receptors form dimers of the same type (homodimers) or with other family members (heterodimers), each combination resulting in different downstream effects. Some of the most advanced targeted agents in development are the EGFR tyrosine kinase inhibitors (EGFR-TKIs), of which ZD1839 ('Iressa') is an example. In Phase II monotherapy trials, oral ZD1839 was well tolerated and demonstrated clinically meaningful antitumor activity and symptom relief in pretreated patients with advanced NSCLC. Preclinical studies have suggested that the antitumor activity of ZD1839 does not depend on the level of EGFR expression. Furthermore, in addition to an effect on EGFR signaling, treatment with ZD1839 as well as with other quinazoline EGFR-TKIs, may also affect signaling of other ErbB family members. EGFR-TKIs have been shown in preclinical studies to increase the efficacy of cytotoxic drugs and Phase III trials of such combinations are ongoing. On the basis that different signal transduction pathways contribute to the control of tumor growth, future therapeutic approaches are likely to involve combination of different targeted agents.

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“…AKT is a major target of ErbB-signaling, speci®cally found downstream of ErbB3 or ErbB4 and perhaps also ErbB1 signaling complexes, via the activation of PI3 kinase (Elenius et al, 1999;Liu et al, 1999;Moscatello et al, 1998;Prigent and Gullick, 1994;Waterman et al, 1999). AKT activity was down-regulated in cell lines immunodepleted for ErbB2, thus providing an indirect posttranscriptional link between ErbB expression, PKB activation and cyclin D levels Neve et al, 2000).…”

Section: The Cyclin D Connectionmentioning

confidence: 99%

Molecular mechanisms underlying ErbB2/HER2 action in breast cancer

2000

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Overexpression of ErbB2, a receptor-like tyrosine kinase, is shared by several types of human carcinomas. In breast tumors the extent of overexpression has a prognostic value, thus identifying the oncoprotein as a target for therapeutic strategies. Already, antibodies to ErbB2 are used in combination with chemotherapy in the treatment of metastasizing breast cancer. The mechanisms underlying the oncogenic action of ErbB2 involve a complex network in which ErbB2 acts as a ligand-less signaling subunit of three other receptors that directly bind a large repertoire of stroma-derived growth factors. The major partners of ErbB2 in carcinomas are ErbB1 (also called EGFR) and ErbB3, a kinase-defective receptor whose potent mitogenic action is activated in the context of heterodimeric complexes. Why ErbB2-containing heterodimers are relatively oncopotent is a function of a number of processes. Apparently, these heterodimers evade normal inactivation processes, by decreasing the rate of ligand dissociation, internalizing relatively slowly and avoiding the degradative pathway by returning to the cell surface. On the other hand, the heterodimers strongly recruit survival and mitogenic pathways such as the mitogen-activated protein kinases and the phosphatidylinositol 3-kinase. Hyper-activated signaling through the ErbB-signaling network results in dysregulation of the cell cycle homeostatic machinery, with upregulation of active cyclin-D/CDK complexes. Recent data indicate that cell cycle regulators are also linked to chemoresistance in ErbB2-dependent breast carcinoma. Together with D-type cyclins, it seems that the CDK inhibitor p21 Waf1 plays an important role in evasion from apoptosis. These recent ®ndings herald a preliminary understanding of the output layer which connects elevated ErbB-signaling to oncogenesis and chemoresistance. Oncogene (2000) 19, 6102 ± 6114.

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Characterization of a naturally occurring ErbB4 isoform that does not bind or activate phosphatidyl inositol 3-kinase

Cited by 151 publications

References 55 publications

Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Elevated neuregulin-1 and ErbB4 protein in the prefrontal cortex of schizophrenic patients

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs): Simple drugs with a complex mechanism of action?

Molecular mechanisms underlying ErbB2/HER2 action in breast cancer

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