Dopamine D2 Receptor-mediated Epidermal Growth Factor Receptor Transactivation through a Disintegrin and Metalloprotease Regulates Dopaminergic Neuron Development via Extracellular Signal-related Kinase Activation

Yoon, Sehyoun; Baik, Ja Hyun

doi:10.1074/jbc.m113.461202

Cited by 39 publications

(29 citation statements)

References 30 publications

(37 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Previous reports suggest that DRD2 signaling leads to ERK activation [23-25, 32]. We hypothesized that this signaling may contribute to the pro-proliferative effect of DRD2.…”

Section: Resultsmentioning

confidence: 89%

Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma

et al. 2014

View full text Add to dashboard Cite

Glioblastoma remains one of the deadliest of human cancers, with most patients succumbing to the disease within two years of diagnosis. The available data suggest that simultaneous inactivation of critical nodes within the glioblastoma molecular circuitry will be required for meaningful clinical efficacy. We conducted parallel genome-wide shRNA screens to identify such nodes and uncovered a number of G-Protein Coupled Receptor (GPCR) neurotransmitter pathways, including the Dopamine Receptor D2 (DRD2) signaling pathway. Supporting the importance of DRD2 in glioblastoma, DRD2 mRNA and protein expression were elevated in clinical glioblastoma specimens relative to matched non-neoplastic cerebrum. Treatment with independent si-/shRNAs against DRD2 or with DRD2 antagonists suppressed the growth of patient-derived glioblastoma lines both in vitro and in vivo. Importantly, glioblastoma lines derived from independent genetically engineered mouse models (GEMMs) were more sensitive to haloperidol, an FDA approved DRD2 antagonist, than the premalignant astrocyte lines by approximately an order of magnitude. The pro-proliferative effect of DRD2 was, in part, mediated through a GNAI2/Rap1/Ras/ERK signaling axis. Combined inhibition of DRD2 and Epidermal Growth Factor Receptor (EGFR) led to synergistic tumoricidal activity as well as ERK suppression in independent in vivo and in vitro glioblastoma models. Our results suggest combined EGFR and DRD2 inhibition as a promising strategy for glioblastoma treatment.

show abstract

“…Previous reports suggest that DRD2 signaling leads to ERK activation [23-25, 32]. We hypothesized that this signaling may contribute to the pro-proliferative effect of DRD2.…”

Section: Resultsmentioning

confidence: 89%

Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma

et al. 2014

View full text Add to dashboard Cite

show abstract

“…These D2-type autoreceptors represent either somatodendritic autoreceptors, known to dampen neuronal excitability (Lacey et al, 1987, 1988; Chiodo and Kapatos, 1992), or terminal autoreceptors, which mostly decrease DA synthesis and packaging (Onali et al, 1988; Pothos et al, 1998), but also inhibit impulse-dependent DA release (Cass and Zahniser, 1991; Kennedy et al, 1992; Congar et al, 2002). Therefore, the principal role of these autoreceptors is the inhibition and modulation of overall DA neurotransmission; however, it has been suggested that in the embryonic stage, the D2-type autoreceptor could have a different function in DA neuronal development (Kim et al, 2006, 2008; Yoon et al, 2011; Yoon and Baik, 2013). Thus, the cellular and molecular role of these presynaptic D2 receptors needs to be explored further.…”

Section: Dopamine Receptorsmentioning

confidence: 99%

“…D2 receptor-mediated ERK activation was found to be dependent on Gα i protein coupling, and it appears thatit requires the transactivation of receptor tyrosine kinase, which activates downstream signaling to finally activate ERK (Choi et al, 1999; Kim et al, 2004; Wang et al, 2005; Yoon et al, 2011; Yoon and Baik, 2013). Arrestin has been also suggested to contribute to D2 receptor-mediated ERK activation (Beom et al, 2004; Kim et al, 2004), which can activate MAPK signaling by mobilizing clathrin-mediated endocytosis in a β-arrestin/dynamin-dependent manner (Kim et al, 2004).…”

Section: Da-mediated Signaling In Activation Of Mitogen-activated Promentioning

confidence: 99%

Dopamine Signaling in reward-related behaviors

Baik

2013

Front. Neural Circuits

Self Cite

389

275

View full text Add to dashboard Cite

Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

show abstract

“…For example, using primary dopaminergic mesencephalic cultures, we have shown that pharmacological inhibition of ERK5, and to a lesser extent ERK1 and 2, resulted in a significant loss of viability of dopaminergic neurons at day in vitro (DIV) 2, 4, 6, and 8 (Parmar et al, 2014). Moreover, others have shown that the regulation of dopaminergic neuronal development is regulated by D2 receptor‐mediated ERK activation (Kim et al, 2006; Yoon et al, 2011; Yoon and Baik, 2013). These data suggest that ERK pathways are necessary for basal survival of dopaminergic neurons during early time points and may play crucial role in the development of dopaminergic brain regions.…”

Section: Introductionmentioning

confidence: 99%

ERK1, 2, and 5 expression and activation in dopaminergic brain regions during postnatal development

Parmar

Jaumotte

Zigmond

et al. 2015

Intl J of Devlp Neuroscience

View full text Add to dashboard Cite

Degeneration and dysfunctioning of dopaminergic neurons in the midbrain have been associated with serious neurodegenerative and neuropsychiatric disorders. Elucidating the underlying neurobiology of these neurons during early postnatal development may provide important information regarding the etiology of these disorders. Cellular signaling pathways have been shown to regulate postnatal neuronal development. Among several signaling pathways, extracellular-regulated mitogen kinases (ERK) 1, 2, and 5 have been shown to be crucial for the survival and function of dopaminergic neurons. In this study, the basal expression and activation of ERK1, 2, and 5 were studied during postnatal development in regions rich in DA cells and terminals. In the striatum (STR) and ventral mesencephalon regions of the substantia nigra (SN) and ventral tegmental area (VTA), ERK5 expression and activation were high during early postnatal days and declined with aging. Interestingly, sharp increases in phosphorylated or activated ERK1 and ERK2 were observed at postnatal day (PND) 7 in the SN and VTA. In contrast, in the STR, the levels of phosphorylated ERK1 and 2 were significantly higher at PND0 than at any other PND examined. Overall, the understanding of alterations in ERK signaling in regions rich in DA cells and DA terminals during postnatal neuronal development may provide information about their role in regulation of dopamine neuronal development which may ultimately provide insight into the underlying mechanisms of dopamine neurodegeneration.

show abstract

Dopamine D2 Receptor-mediated Epidermal Growth Factor Receptor Transactivation through a Disintegrin and Metalloprotease Regulates Dopaminergic Neuron Development via Extracellular Signal-related Kinase Activation

Cited by 39 publications

References 30 publications

Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma

Genome-wide shRNA screen revealed integrated mitogenic signaling between dopamine receptor D2 (DRD2) and epidermal growth factor receptor (EGFR) in glioblastoma

Dopamine Signaling in reward-related behaviors

ERK1, 2, and 5 expression and activation in dopaminergic brain regions during postnatal development

Contact Info

Product

Resources

About