Cell Death or Survival Promoted by Alternative Isoforms of ErbB4

Sundvall, Maria; Veikkolainen, Ville; Kurppa, Kari J.; Salah, Zaidoun; Tvorogov, Denis; Zoelen, Everardus J. van; Aqeilan, Rami; Elenius, Klaus

doi:10.1091/mbc.e10-04-0332

Cited by 57 publications

(65 citation statements)

References 48 publications

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“…Six hours after transfection, culture medium was replaced by DMEM without FBS. Cells were starved for 18 h, stimulated with 50 ng/mL neuregulin 1-beta 1 EGF domain protein (R&D Systems) for 10 min at 37°C (24), and lysed in RIPA buffer supplemented with Halt Protease and Phosphatase Inhibitor Mixture (all from Thermo Scientific). Phosphorylation levels of ErbB4 splice variants were assessed by Western blotting with a phosphospecific ErbB4 antibody (rabbit, 1:1,000; Cell Signaling).…”

Section: Methodsmentioning

confidence: 99%

“…Moreover, ErbB4 transcripts are alternatively spliced at two loci, generating four different splice variants with distinct downstream signaling pathways (21). Although their functional consequences are not known in PV interneurons, ErbB4 splice variants display different levels of tyrosine kinase activity and exert different physiological effects in nonneuronal cells (22)(23)(24), suggesting that the effect of ErbB4 signaling could be modulated by alternative splicing. Thus, shifts in the expression level and/or splicing of ErbB4 in PV interneurons during adolescence might function as a developmental switch regulating the pruning of excitatory synapses on these neurons.…”

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confidence: 99%

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Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

Chung

Wills

Fish

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Working memory requires efficient excitatory drive to parvalbuminpositive (PV) interneurons in the primate dorsolateral prefrontal cortex (DLPFC). Developmental pruning eliminates superfluous excitatory inputs, suggesting that working memory maturation during adolescence requires pruning of excitatory inputs to PV interneurons. Therefore, we tested the hypothesis that excitatory synapses on PV interneurons are pruned during adolescence. The density of excitatory synapses, defined by overlapping vesicular glutamate transporter 1-positive (VGlut1+) and postsynaptic density 95-positive (PSD95+) puncta, on PV interneurons was lower in postpubertal relative to prepubertal monkeys. In contrast, puncta levels of VGlut1 and PSD95 proteins were higher in postpubertal monkeys and positively predicted activity-dependent PV levels, suggesting a greater strength of the remaining synapses after pruning. Because excitatory synapse number on PV interneurons is regulated by erb-b2 receptor tyrosine kinase 4 (ErbB4), whose function is influenced by alternative splicing, we tested the hypothesis that pruning of excitatory synapses on PV interneurons is associated with developmental shifts in ErbB4 expression and/or splicing. Pan-ErbB4 expression did not change, whereas the minor-to-major splice variant ratios increased with age. In cell culture, the major, but not the minor, variant increased excitatory synapse number on PV interneurons and displayed greater kinase activity than the minor variant, suggesting that the effect of ErbB4 signaling in PV interneurons is mediated by alternative splicing. Supporting this interpretation, in monkey DLPFC, higher minor-to-major variant ratios predicted lower PSD95+ puncta density on PV interneurons. Together, our findings suggest that ErbB4 splicing may regulate the pruning of excitatory synapses on PV interneurons during adolescence.synaptic pruning | parvalbumin interneuron | ErbB4 | alternative splicing | schizophrenia I n primates, certain complex cognitive processes, such as working memory, depend in part on the proper activation of specific neural circuits in the dorsolateral prefrontal cortex (DLPFC) (1). In both monkeys and humans, recruitment of DLPFC activity and performance during working memory tasks continue to improve through adolescence (2-4). During this period, excitatory synapses and their principal targets, pyramidal neuron dendritic spines, massively decline in number in the primate DLPFC (5-8). Synaptic pruning is thought to eliminate unwanted or imprecise connections and to strengthen the remaining connections (9, 10), suggesting that this process could contribute to the maturation of working memory function during adolescence.Working memory is thought to emerge from oscillatory activity of DLPFC neurons at gamma frequency (30-80 Hz) (11), which requires the activity of local GABAergic interneurons that express the calcium binding protein parvalbumin (PV) (12, 13). During working memory tasks, excitation from pyramidal neurons recruits PV interneurons, which in turn pro...

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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

Chung

Wills

Fish

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Glutathione S-transferase Pull-down Assay-GST fusion proteins have been described (11). FLAG-tagged PIAS proteins, STAT5a, or Wwox-Myc were transiently expressed in COS-7 cells, and the GST pull-down assay was performed as described previously (28).…”

Section: Methodsmentioning

confidence: 99%

Protein Inhibitor of Activated STAT3 (PIAS3) Protein Promotes SUMOylation and Nuclear Sequestration of the Intracellular Domain of ErbB4 Protein

Sundvall

Korhonen

Vaparanta

et al. 2012

Journal of Biological Chemistry

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Background: Mechanisms regulating nuclear translocation of the ErbB4 intracellular domain (ICD) are unclear. Results: PIAS3 interacts with ErbB4, sequesters ICD into the nucleus, and represses its nuclear signaling. Conclusion: PIAS3 is a regulator of subcellular localization and nuclear functions of ErbB4. Significance: A novel mechanism controlling the signaling of an ICD of a receptor tyrosine kinase in the nucleus is described.

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“…Mammary cell lines expressing exogenous CYT-2 ICD grow more rapidly than the same cell line expressing CYT-1 ICD (Muraoka-Cook et al, 2009). In a mouse fibroblast cell line, the ICD of JM-a CYT-2 was found to interact with AP-2 to positively regulate the platelet-derived growth factor receptor-alpha (PDGFA) promoter leading to cell proliferation (Sundvall et al, 2010). Taken together with these observations, our data suggests that cardiomyocytes require different isoforms to proliferate or hypertrophy.…”

Section: Discussionsupporting

confidence: 53%

Investigations into the role of the ErbB4 receptor in cardiomyocyte hypertrophy and adult cardiac function

Wang¹

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ErbB receptors (ErbB1 -ErbB4) are a subfamily of tyrosine kinase receptors that regulate cell proliferation and differentiation. It has been proposed that the ErbB1 subtype is transactivated by Ang II to mediate cardiac hypertrophy. However, whether other ErbB receptors, in particular the abundant subtype ErbB4, are involved in this process is not known. ErbB4 has four isoforms due to alternative splicing, each of which might play a distinct role in regulating cell activity. However, the role of individual ErbB4 isoforms in hypertrophic signalling has not been investigated. In addition, ErbB4 activation is critical for cardiac development, cardiomyocyte survival in various rodent models of cardiovascular pathologies. However, the physiological role of ErbB4 in the adult heart remains poorly understood. The overall aim of my PhD project is to examine the role of the ErbB4 receptor in mediating hypertrophic growth of cardiomyocytes in vitro, and maintenance of the adult heart in vivo.To investigate the role of ErbB1, ErbB2 and ErbB4 in mediating hypertrophy, I inhibited individual ErbB receptors in primary neonatal rat ventricular cardiomyocytes using RNA interference or a pharmacological inhibitor (AG1478). Hypertrophy induced with Ang II (100 nM) or NRG1 (10 nM) was assessed by measuring the promoter activity of hypertrophic genes, ERK1/2 activation, and hypertrophic growth. The NRG1-induced hypertrophy was reduced by down-regulation of Following the studies above, I investigated whether the different ErbB4 isoforms had any functional differences in the cardiomyocytes. Irrespective of any changes in total ErbB4 mRNA levels, expression of the non-cleavable JM-b isoform was always predominant in adult heart in both physiological and pathological conditions. Although the cleavable isoform JM-a was detectable, it is not cleaved in cardiomyocytes. I replaced the endogenous ErbB4 with exogenous individual isoform in cardiomyocytes and found that all four isoforms of ErbB4 could mediate the NRG1-induced hypertrophic signalling. This suggests that the hypertrophy is triggered by a common feature of the four isoforms (ostensibly the kinase activity), and appears independent of isoformspecific features, such as the cleavable domain.To investigate the physiological function of ErbB4 in adult heart, we adopted the tamoxifeniii inducible αMHC-MerCreMer/loxP system to induce ErbB4 deletion from cardiomyocytes in the adult mouse. The expression of ErbB4 was reduced by ~ 90% at 10 days after tamoxifen treatment. Echocardiography revealed no differences in cardiac function (fractional shortening) betweenErbB4-conditional knockout (ErbB4-cKO) and control groups at 3-4 months after deletion of ErbB4. However, the heart weight was increased in ErbB4-cKO animals. Interestingly, there is no change in cardiac structure (cardiomyocyte size and cardiac fibrosis) or the expression of genes associated with pathological hypertrophy. This suggests that the cardiac hypertrophy observed following ErbB4 deletion may be physiological, a...

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Cell Death or Survival Promoted by Alternative Isoforms of ErbB4

Cited by 57 publications

References 48 publications

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

Developmental pruning of excitatory synaptic inputs to parvalbumin interneurons in monkey prefrontal cortex

Protein Inhibitor of Activated STAT3 (PIAS3) Protein Promotes SUMOylation and Nuclear Sequestration of the Intracellular Domain of ErbB4 Protein

Investigations into the role of the ErbB4 receptor in cardiomyocyte hypertrophy and adult cardiac function

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