Cdk5 Phosphorylates Dopamine D2 Receptor and Attenuates Downstream Signaling

Jeong, Jong Ju; Park, Young-Un; Kim, Dae-Kyum; Lee, Saebom; Kwak, Yongdo; Lee, Seol-Ae; Lee, Haeryun; Suh, Yoo-Hun; Gho, Yong Song; Hwang, Daehee

doi:10.1371/journal.pone.0084482

Cited by 27 publications

(21 citation statements)

References 48 publications

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“…Dopamine agonists can normalize prolactin secretion in 80 to 90% of microadenoma patients and 70% of macroadenoma patients. CDK5 may phosphorylate the dopamine D2 receptor and attenuate downstream signaling [30]. The data suggest that CDK5 might also regulate DA resistance and tumor growth in prolactin pituitary adenomas.…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas

Xie

Liu

Wu³

et al. 2016

Oncotarget

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Pituitary adenomas constitute 15-20% of intracranial neoplasms. Previously we reported that cyclin-dependent kinase 5 (CDK5) is upregulated in pituitary tumors associated with activating protein p35, and plays an essential role in pituitary adenomas progression. Here we explored the mechanisms of CDK5 signaling in prolactin pituitary adenomas. Our data indicate that p35 expression and CDK5 activity are both significantly increased in human invasive prolactin pituitary adenomas as compared to noninvasive forms of pituitary adenomas. Inhibition of CDK5 activity suppressed cell migration and invasive ability in GH3 rat pituitary cells. We identified that CDK5 phosphorylates serine 229 residue (Ser-229) of kinase insert domain receptor (KDR), also known as VEGFR-2, in prolactin pituitary adenomas. Phosphorylation of Ser-229 is required for proper KDR surface localization. Phosphorylated Ser-229 in KDR (pSer-229) levels are significantly higher in noninvasive and invasive prolactin pituitary adenomas compared to normal pituitary tissues. In addition, our data indicated that higher KDR pSer-229 correlates with worse prognosis in patients with prolactin pituitary adenomas. In summary, our results illustrated that CDK5-mediated KDR phosphorylation controls prolactin pituitary adenoma progression and KDR pSer-229 serves as a potential prognostic biomarker for both noninvasive and invasive pituitary adenomas.

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Section: Discussionmentioning

confidence: 99%

Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas

Xie

Liu

Wu³

et al. 2016

Oncotarget

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“…An association of p25 with Cdk5 could form a stable complex, p25/Cdk5, which induces various pathological events that are Aβ formation, tau hyperphosphorylation, synaptic plasticity, neuronal cell apoptosis, reactivation of cell cycle and oxidative stress and mitochondrial dysfunction, eventually leading to neurons death oxygen deprivation, which acts as a new hypoxiamediated signaling pathway [32]. Cdk5-mediated phosphorylation of S321 inhibits DRD2 function, which is a key receptor that mediates dopamine-associated brain functions such as mood, reward, and emotion [33].…”

Section: Cdk5 Is Essential For Neuronal Survivalmentioning

confidence: 99%

“…Preliminary findings have already shown that Cdk5 is also pivotal to postsynaptic compartment, where exists a lot of substrates of Cdk5, such as NMDAR [90], PSD-95 [91], DARPP-32 [42], and dopamine D2 receptor [33]. Cdk5 can modulate the function of NMDAR, which is related to the induction of some forms of synaptic plasticity; for example, the NMDAR-dependent Hebbian long-term potentiation (LTP) and long-term depression (LTD).…”

Section: Cdk5 Modulates Synaptic Plasticitymentioning

confidence: 99%

The Role of Cdk5 in Alzheimer’s Disease

et al. 2015

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Alzheimer's disease (AD) is known as the most fatal chronic neurodegenerative disease in adults along with progressive loss of memory and other cognitive function disorders. Cyclin-dependent kinase 5 (Cdk5), a unique member of the cyclin-dependent kinases (Cdks), is reported to intimately associate with the process of the pathogenesis of AD. Cdk5 is of vital importance in the development of CNS and neuron movements such as neuronal migration and differentiation, synaptic functions, and memory consolidation. However, when neurons suffer from pathological stimuli, Cdk5 activity becomes hyperactive and causes aberrant hyperphosphorylation of various substrates of Cdk5 like amyloid precursor protein (APP), tau and neurofilament, resulting in neurodegenerative diseases like AD. Deregulation of Cdk5 contributes to an array of pathological events in AD, ranging from formation of senile plaques and neurofibrillary tangles, synaptic damage, mitochondrial dysfunction to cell cycle reactivation as well as neuronal cell apoptosis. More importantly, an inhibition of Cdk5 activity with inhibitors such as RNA inference (RNAi) could protect from memory decline and neuronal cell loss through suppressing β-amyloid (Aβ)-induced neurotoxicity and tauopathies. This review will briefly describe the above-mentioned possible roles of Cdk5 in the physiological and pathological mechanisms of AD, further discussing recent advances and challenges in Cdk5 as a therapeutic target.

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“…Dopamine attenuates protein kinase A (PKA) activation that is initiated by downregulating the cellular level of cyclic AMP (cAMP). In addition, PKA upregulates the NF-κB pathway by phosphorylating p65 on serine 276 [17,18]. Moreover, activation of DRD2 suppresses nuclear translocation of NF-κB in the intracerebral hemorrhage (ICH) mouse model [19].…”

Section: Introductionmentioning

confidence: 99%

Overexpressed D2 Dopamine Receptor Inhibits Non-Small Cell Lung Cancer Progression through Inhibiting NF-κB Signaling Pathway

Zhang

Deng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Non-small cell lung cancer (NSCLC) is one of the deadliest cancers worldwide. Dopamine receptor D2 (DRD2) has multiple roles in clinical progression of NSCLC and functional maintenance of cancer cells. However, little is known about the molecular mechanism. Here, we clarified whether DRD2 inhibits lung cancer progression and identified the underlying downstream signaling. Methods: DRD2 mRNA and protein levels were detected in clinical specimens by qRT-PCR and immunohistochemistry, respectively. MTT and colony formation assays were applied to analyze cell proliferation. The underlying molecular mechanism was identified by dual luciferase, western blot, qRT-PCR, cAMP detection, immunoprecipitation, and chromatin immunoprecipitation assays. A murine NSCLC model was used to clarify the role of DRD2 in tumor cell proliferation. Results: We found that DRD2 ablated tumor cell growth. DRD2 expression in NSCLC tissues was lower than in adjacent normal lung tissues. Moreover, DRD2 mRNA and protein levels in NSCLC were negatively correlated with the tumor size, TNM status, and patient overall survival. In vitro experiments showed that disruption of DRD2 promoted the proliferation of NSCLC cell lines A549 and SK-MES-1 by inhibiting the NF-κB signaling pathway. Furthermore, DRD2 overexpression not only blocked lipopolysaccharide-induced A549 and SK-MES-1 cell proliferation and growth, but also inhibited the tumorigenesis in murine xenograft models. Conclusion: These results indicate that DRD2 may be a potential therapeutic target for lung cancer patients with high DRD2 expression by ablating the NF-κB signaling pathway.

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Cdk5 Phosphorylates Dopamine D2 Receptor and Attenuates Downstream Signaling

Cited by 27 publications

References 48 publications

Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas

Phosphorylation of kinase insert domain receptor by cyclin-dependent kinase 5 at serine 229 is associated with invasive behavior and poor prognosis in prolactin pituitary adenomas

The Role of Cdk5 in Alzheimer’s Disease

Overexpressed D2 Dopamine Receptor Inhibits Non-Small Cell Lung Cancer Progression through Inhibiting NF-κB Signaling Pathway

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