p21-activated Kinase 3 (PAK3) Protein Regulates Synaptic Transmission through Its Interaction with the Nck2/Grb4 Protein Adaptor

Thévenot, Emmanuelle; Moreau, Alexandre; Rousseau, Véronique; Combeau, Gaëlle; Domenichini, Florence; Jacquet, Claire; Goupille, Olivier; Amar, Muriel; Kreis, Patricia; Fossier, Philippe; Barnier, Jean-Vianney

doi:10.1074/jbc.m111.262246

Cited by 32 publications

(21 citation statements)

References 55 publications

(95 reference statements)

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“…The pFLAG-PAK3a-R436E-K437D-K297L was digested by KpnI/XbaI and the fragment obtained was cloned in the pcDNA3-HA vector, leading to the pcDNA3-HA-PAK3a-R436E-K437D-K297L plasmid. PCR amplifications were performed from the pFLAG-PAK3a-K297L and the pFLAG-PAK3a-R436E-K437D using the oligonucleotides set 3. pLex and pGAD plasmids previously were previously described (5). PCR products were digested by BamHI/SalI and the fragments obtained were inserted in the pLex vector to obtain the pLex-PAK3-(232-544) plasmid (named pLex-PAK3-Cter) and the pLex-PAK3-R436E-K437D-(232-544) plasmid (named pLex-PAK3-Cter-R436E-K437D), respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Cell Line and Neuron Culture, Immunocytochemistry, and Imaging-HeLa cell cultures, primary cultures of dissociated hippocampal neurons and transfections were previously described (5). For HeLa cells, PAK-transfected cells were fixed after 24 h and triple immunolabeled using FLAG, HA, and paxillin antibodies, followed by anti-rabbit-FITC-, anti-rat-TRITC-and anti-mouse-Alexa-633-conjugated secondary antibodies, respectively.…”

Section: Methodsmentioning

confidence: 99%

“…Immunoprecipitation was then performed overnight at 4°C by adding protein G-agarose and appropriate PAK antibodies. Samples were resolved by electrophoresis and Western blotting as previously described (5 Yeast Two-hybrid Assay, Histidine Test, and ␤-Galactosidase Activity-The two-hybrid assay was applied according to standard procedures. L40 yeasts strain (L40 Mata, Trp-1, Leu-2, His-3, lys::(lexAop)4-HIS3, ura3::(LexAop)8-LacZ), were co-transfected with pLex and pGAD constructs by the lithium acetate method and transformants were grown on appropriate selective medium.…”

Section: Methodsmentioning

confidence: 99%

“…Interestingly, PAK1 protein is also involved in synaptic plasticity via regulation of cofilin phosphorylation and actin cytoskeleton modeling (40) whereas PAK3 probably acts through other pathways involving CREB and Nck2 (5,30). A recent study that characterized the pak1/ pak3 double KO mice pointed out new neuronal defects due to an impaired post-natal brain growth (41).…”

Section: Molecular Mechanisms Of Regulation Of Pak3-kinasementioning

confidence: 99%

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The p21-activated Kinase PAK3 Forms Heterodimers with PAK1 in Brain Implementing Trans-regulation of PAK3 Activity

Combeau¹,

Kreis²,

Domenichini³

et al. 2012

Journal of Biological Chemistry

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Molecular Mechanisms Of Regulation Of Pak3-kinasementioning

confidence: 99%

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The p21-activated Kinase PAK3 Forms Heterodimers with PAK1 in Brain Implementing Trans-regulation of PAK3 Activity

Combeau¹,

Kreis²,

Domenichini³

et al. 2012

Journal of Biological Chemistry

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“…PAK3 is a serine/threonine kinase that is involved in several processes, including actin organization and migration (AriasRomero and Chernoff, 2008;Holderness Parker et al, 2013), embryonic development of the brain and neuron ( Jaffer and Chernoff, 2002), synaptic transmission (Thevenot et al, 2011), dendrite spine formation, and synaptic plasticity (Kreis et al, 2007;Node-Langlois et al, 2006). PAK3 shows significant expression in the brain, more specifically in the hippocampus, cerebral cortex, and neurons (Boda et al, 2004).…”

Section: Discussionmentioning

confidence: 99%

Next-Generation Sequencing Reveals Novel Mutations in X-linked Intellectual Disability

Muthusamy

Selvan²,

Nguyen³

et al. 2017

OMICS: A Journal of Integrative Biology

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Robust diagnostics for many human genetic disorders are much needed in the pursuit of global personalized medicine. Next-generation sequencing now offers new promise for biomarker and diagnostic discovery, in developed as well as resource-limited countries. In this broader global health context, X-linked intellectual disability (XLID) is an inherited genetic disorder that is associated with a range of phenotypes impacting societies in both developed and developing countries. Although intellectual disability arises due to diverse causes, a substantial proportion is caused by genomic alterations. Studies have identified causal XLID genomic alterations in more than 100 protein-coding genes located on the X-chromosome. However, the causes for a substantial number of intellectual disability and associated phenotypes still remain unknown. Identification of causative genes and novel mutations will help in early diagnosis as well as genetic counseling of families. Advent of next-generation sequencing methods has accelerated the discovery of new genes involved in mental health disorders. In this study, we analyzed the exomes of three families from India with nonsyndromic XLID comprising seven affected individuals. The affected individuals had varying degrees of intellectual disability, microcephaly, and delayed motor and language milestones. We identified potential causal variants in three XLID genes, including PAK3 (V294M), CASK (complex structural variant), and MECP2 (P354T). Our findings reported in this study extend the spectrum of mutations and phenotypes associated with XLID, and calls for further studies of intellectual disability and mental health disorders with use of next-generation sequencing technologies.

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PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth

et al. 2021

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Purpose Gliomas are the most lethal adult primary brain cancers. Recent advances in their molecular characterization have contributed to a better understanding of their pathophysiology, but there is still a need to identify key genes controlling glioma cell proliferation and differentiation. The p21-activated kinases PAK1 and PAK2 play essential roles in cell division and brain development and are well-known oncogenes. In contrast, the role of PAK3 in cancer is poorly understood. It is known, however that this gene is involved in brain ontogenesis and has been identified as a gene of the proneural subtype signature in glioblastomas. Methods To better understand the role of PAK kinases in the pathophysiology of gliomas, we conducted expression analyses by querying multiple gene expression databases and analyzing primary human glioma samples. We next studied PAK3 expression upon differentiation in patient-derived cell lines (PDCLs) and the effects of PAK3 inhibition by lentiviral-mediated shRNA on glioma cell proliferation, differentiation and tumor growth. ResultsWe show that contrary to PAK1 and PAK2, high PAK3 expression positively correlates with a longer survival of glioma patients. We also found that PAK3 displays differential expression patterns between glioma sub-groups with a higher expression in 1p/19q-codeleted oligodendrogliomas, and is highly expressed in tumors and PDCLs of the proneural subtype. In PDCLs, high PAK3 expression negatively correlated with proliferation and positively correlated with neuronal differentiation. Inhibition of PAK3 expression increased PDCL proliferation and glioma tumor growth in nude mice. Conclusions Our results indicate that PAK3 plays a unique role among PAKs in glioma development and may represent a potential therapeutic target.

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p21-activated Kinase 3 (PAK3) Protein Regulates Synaptic Transmission through Its Interaction with the Nck2/Grb4 Protein Adaptor

Cited by 32 publications

References 55 publications

The p21-activated Kinase PAK3 Forms Heterodimers with PAK1 in Brain Implementing Trans-regulation of PAK3 Activity

The p21-activated Kinase PAK3 Forms Heterodimers with PAK1 in Brain Implementing Trans-regulation of PAK3 Activity

Next-Generation Sequencing Reveals Novel Mutations in X-linked Intellectual Disability

PAK3 is a key signature gene of the glioma proneural subtype and affects its proliferation, differentiation and growth

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