Phosphorylation of the Par Polarity Complex Protein Par3 at Serine 962 Is Mediated by Aurora A and Regulates Its Function in Neuronal Polarity

Khazaei, Mohammad Rasoul; Püschel, Andreas W.

doi:10.1074/jbc.m109.055897

Cited by 42 publications

(31 citation statements)

References 40 publications

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“…Because two aPKC‐binding variants showed disruption of tight junction formation, we transfected siRNA into human NPCs to develop an in vitro cellular model with PARD3 knockdown, and then examine the phenotypic characteristics of the NPCs. The PARD3/PARD6 complex was reported to display apical polarity in human neural progenitors, which is different from what was seen in MDCK cells [Wolf, et al., ; Khazaei and Puschel, ]. We confirmed that PARD3 was apically localized on NPCs undergoing mirror‐symmetry divisions (white arrow in Supp.…”

Section: Resultssupporting

confidence: 66%

Rare DeleteriousPARD3Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation

Chen

Gao

et al. 2017

Human Mutation

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Increasing evidence that mutation of planar cell polarity (PCP) genes contributes to human cranial NTD susceptibility prompted us to hypothesize that rare variants of genes in the core apical–basal polarity (ABP) pathway are risk factors for cranial NTDs. In this study, we screened for rare genomic variation of PARD3 in 138 cranial NTD cases and 274 controls. Overall, the rare deleterious variants of PARD3 were significantly associated with increased risk for cranial NTDs (11/138 vs.7/274, p<0.05, OR=3.3). These NTD-specific variants were significantly enriched in the aPKC-binding region (6/138 vs. 0/274, p<0.01). The East Asian cohort in the ExAC database and another Chinese normal cohort further supported this association. Over-expression analysis in HEK293T and MDCK cells confirmed abnormal aPKC binding or interaction for two PARD3 variants (p.P913Q and p.D783G), resulting in defective tight junction formation via disrupted aPKC binding. Functional analysis in human neural progenitor cells and chick embryos revealed that PARD3 knockdown gave rise to abnormal cell polarity and compromised the polarization process of neuroepithelial tissue. Our studies suggest that rare deleterious variants of PARD3 in the aPKC-binding region contribute to human cranial NTDs, possibly by disrupting apical tight junction formation and subsequent polarization process of the neuroepithelium.

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Section: Resultssupporting

confidence: 66%

Rare DeleteriousPARD3Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation

Chen

Gao

et al. 2017

Human Mutation

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“…A hypomorphic alíele of Aurora A impairs asymmetric localization of the basal asymmetric marker Numb and increases the number of symmetric cell divisions. These defects are thought to be caused by altered dynein-dependent spindle orientation and delocalization of specific cortical markers such as aPKC or Numb recruited through the Aurora A-dependent phosphorylation of Dlg(Pins), Par-3, and Par-6 (158, 169,187,353). Aurora B may also play a role in asymmetric cell division as its CPC partner INCENP is required for the asymmetric segregation of Prospero during asymmetric neuroblast division in Drosophila (58).…”

Section: Figurementioning

confidence: 98%

Physiological Relevance of Cell Cycle Kinases

Malumbres

2011

Physiological Reviews

184

136

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The basic biology of the cell division cycle and its control by protein kinases was originally studied through genetic and biochemical studies in yeast and other model organisms. The major regulatory mechanisms identified in this pioneer work are conserved in mammals. However, recent studies in different cell types or genetic models are now providing a new perspective on the function of these major cell cycle regulators in different tissues. Here, we review the physiological relevance of mammalian cell cycle kinases such as cyclin-dependent kinases (Cdks), Aurora and Polo-like kinases, and mitotic checkpoint regulators (Bub1, BubR1, and Mps1) as well as other less-studied enzymes such as Cdc7, Nek proteins, or Mastl and their implications in development, tissue homeostasis, and human disease. Among these functions, the control of self-renewal or asymmetric cell division in stem/progenitor cells and the ability to regenerate injured tissues is a central issue in current research. In addition, many of these proteins play previously unexpected roles in metabolism, cardiovascular function, or neuron biology. The modulation of their enzymatic activity may therefore have multiple therapeutic benefits in human disease.

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“…However, in C. elegans , there is no evidence for AIR-1 to be involved in PLK-1 activation [84]. Alternatively, AIR-1 could control polarity more directly by phosphorylating polarity components, as is the case in D. melanogaster , where Aurora A phosphorylates Par6 and aPKC [88,89], or in mammalian neurons, where Aurora A phosphorylates Par3 [90]. …”

Section: Coupling Cell Polarity and Cell Cycle Progression In Caenorhmentioning

confidence: 99%

Coordinating cell polarity and cell cycle progression: what can we learn from flies and worms?

et al. 2013

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Spatio-temporal coordination of events during cell division is crucial for animal development. In recent years, emerging data have strengthened the notion that tight coupling of cell cycle progression and cell polarity in dividing cells is crucial for asymmetric cell division and ultimately for metazoan development. Although it is acknowledged that such coupling exists, the molecular mechanisms linking the cell cycle and cell polarity machineries are still under investigation. Key cell cycle regulators control cell polarity, and thus influence cell fate determination and/or differentiation, whereas some factors involved in cell polarity regulate cell cycle timing and proliferation potential. The scope of this review is to discuss the data linking cell polarity and cell cycle progression, and the importance of such coupling for asymmetric cell division. Because studies in model organisms such as Caenorhabditis elegans and Drosophila melanogaster have started to reveal the molecular mechanisms of this coordination, we will concentrate on these two systems. We review examples of molecular mechanisms suggesting a coupling between cell polarity and cell cycle progression.

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Phosphorylation of the Par Polarity Complex Protein Par3 at Serine 962 Is Mediated by Aurora A and Regulates Its Function in Neuronal Polarity

Cited by 42 publications

References 40 publications

Rare DeleteriousPARD3Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation

Rare DeleteriousPARD3Variants in the aPKC-Binding Region are Implicated in the Pathogenesis of Human Cranial Neural Tube Defects Via Disrupting Apical Tight Junction Formation

Physiological Relevance of Cell Cycle Kinases

Coordinating cell polarity and cell cycle progression: what can we learn from flies and worms?

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