A chemical-genetics approach to study the role of atypical Protein Kinase C in Drosophila

Studying the function of proteins using genetics in cycling cells is complicated by the fact that there is often a delay between gene inactivation and the time point of phenotypic analysis. This is particularly true when studying kinases that have pleiotropic functions and multiple substrates. neuro...

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Published inDevelopment (Cambridge) Vol. 146; no. 2
Main Authors Hannaford, Matthew, Loyer, Nicolas, Tonelli, Francesca, Zoltner, Martin, Januschke, Jens
Format Journal Article
LanguageEnglish
Published England The Company of Biologists Ltd 15.01.2019
Subjects
Alleles
Animals
Cell Division
Cell Polarity
Drosophila melanogaster - embryology
Drosophila melanogaster - enzymology
Drosophila melanogaster - genetics
Drosophila Proteins - antagonists & inhibitors
Drosophila Proteins - genetics
Drosophila Proteins - metabolism
Embryo, Nonmammalian - cytology
Embryo, Nonmammalian - metabolism
Larva - cytology
Larva - metabolism
Loss of Function Mutation - genetics
Neurons - metabolism
Protein Kinase C - antagonists & inhibitors
Protein Kinase C - genetics
Protein Kinase C - metabolism
RNA Interference
Techniques and Resources
Chemical genetics
Neuroblasts
Drosophila
atypical Protein Kinase C
Asymmetric cell division
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Abstract Studying the function of proteins using genetics in cycling cells is complicated by the fact that there is often a delay between gene inactivation and the time point of phenotypic analysis. This is particularly true when studying kinases that have pleiotropic functions and multiple substrates. neuroblasts (NBs) are rapidly dividing stem cells and an important model system for the study of cell polarity. Mutations in multiple kinases cause NB polarity defects, but their precise functions at particular time points in the cell cycle are unknown. Here, we use chemical genetics and report the generation of an analogue-sensitive allele of atypical Protein Kinase C (aPKC). We demonstrate that the resulting mutant aPKC kinase can be specifically inhibited and Acute inhibition of aPKC during NB polarity establishment abolishes asymmetric localization of Miranda, whereas its inhibition during NB polarity maintenance does not in the time frame of normal mitosis. However, aPKC helps to sharpen the pattern of Miranda, by keeping it off the apical and lateral cortex after nuclear envelope breakdown.
AbstractList Studying the function of proteins using genetics in cycling cells is complicated by the fact that there is often a delay between gene inactivation and the time point of phenotypic analysis. This is particularly true when studying kinases that have pleiotropic functions and multiple substrates. Drosophila neuroblasts (NBs) are rapidly dividing stem cells and an important model system for the study of cell polarity. Mutations in multiple kinases cause NB polarity defects, but their precise functions at particular time points in the cell cycle are unknown. Here, we use chemical genetics and report the generation of an analogue-sensitive allele of Drosophila atypical Protein Kinase C (aPKC). We demonstrate that the resulting mutant aPKC kinase can be specifically inhibited in vitro and in vivo Acute inhibition of aPKC during NB polarity establishment abolishes asymmetric localization of Miranda, whereas its inhibition during NB polarity maintenance does not in the time frame of normal mitosis. However, aPKC helps to sharpen the pattern of Miranda, by keeping it off the apical and lateral cortex after nuclear envelope breakdown.
Studying the function of proteins using genetics in cycling cells is complicated by the fact that there is often a delay between gene inactivation and the timepoint of phenotypic analysis. This is particularly true when studying kinases, that have pleiotropic functions and multiple substrates. Drosophila neuroblasts are rapidly dividing stem cells and an important model system to study cell polarity. Mutations in multiple kinases cause neuroblast polarity defects, but their precise functions at particular time points in the cell cycle are unknown. Here we use chemical genetics and report the generation of an analogue-sensitive (as) allele of Drosophila atypical protein kinase C (aPKC). We demonstrate that the resulting mutant aPKC kinase can be specifically inhibited in vitro and in vivo. Acute inhibition of aPKC during neuroblast polarity establishment abolishes asymmetric localization of Miranda while its inhibition during NB polarity maintenance does not in the time frame of normal mitosis. However, aPKC contributes to sharpen the pattern of Miranda, by keeping it off the apical and lateral cortex after nuclear envelope breakdown.
Studying the function of proteins using genetics in cycling cells is complicated by the fact that there is often a delay between gene inactivation and the time point of phenotypic analysis. This is particularly true when studying kinases that have pleiotropic functions and multiple substrates. Drosophila neuroblasts (NBs) are rapidly dividing stem cells and an important model system for the study of cell polarity. Mutations in multiple kinases cause NB polarity defects, but their precise functions at particular time points in the cell cycle are unknown. Here, we use chemical genetics and report the generation of an analogue-sensitive allele of Drosophila atypical Protein Kinase C (aPKC). We demonstrate that the resulting mutant aPKC kinase can be specifically inhibited in vitro and in vivo . Acute inhibition of aPKC during NB polarity establishment abolishes asymmetric localization of Miranda, whereas its inhibition during NB polarity maintenance does not in the time frame of normal mitosis. However, aPKC helps to sharpen the pattern of Miranda, by keeping it off the apical and lateral cortex after nuclear envelope breakdown. Summary: The generation of an analogue-sensitive allele of aPKC in Drosophila allows dissection of the function of aPKC kinase activity with high specificity and temporal control.
Studying the function of proteins using genetics in cycling cells is complicated by the fact that there is often a delay between gene inactivation and the time point of phenotypic analysis. This is particularly true when studying kinases that have pleiotropic functions and multiple substrates. neuroblasts (NBs) are rapidly dividing stem cells and an important model system for the study of cell polarity. Mutations in multiple kinases cause NB polarity defects, but their precise functions at particular time points in the cell cycle are unknown. Here, we use chemical genetics and report the generation of an analogue-sensitive allele of atypical Protein Kinase C (aPKC). We demonstrate that the resulting mutant aPKC kinase can be specifically inhibited and Acute inhibition of aPKC during NB polarity establishment abolishes asymmetric localization of Miranda, whereas its inhibition during NB polarity maintenance does not in the time frame of normal mitosis. However, aPKC helps to sharpen the pattern of Miranda, by keeping it off the apical and lateral cortex after nuclear envelope breakdown.
Author Loyer, Nicolas
Hannaford, Matthew
Januschke, Jens
Zoltner, Martin
Tonelli, Francesca
AuthorAffiliation 1 Cell and Developmental Biology , School of Life Sciences, University of Dundee , Dow Street, Dundee DD5 1EH , UK
3 Biological Chemistry and Drug Discovery , School of Life Sciences, University of Dundee , Dow Street, Dundee DD5 1EH , UK
2 MRC Protein Phosphorylation and Ubiquitylation Unit , School of Life Sciences, University of Dundee , Dow Street, Dundee DD5 1EH , UK
AuthorAffiliation_xml – name: 3 Biological Chemistry and Drug Discovery , School of Life Sciences, University of Dundee , Dow Street, Dundee DD5 1EH , UK
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– name: 2 MRC Protein Phosphorylation and Ubiquitylation Unit , School of Life Sciences, University of Dundee , Dow Street, Dundee DD5 1EH , UK
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Issue 2
Keywords Chemical genetics
Neuroblasts
Drosophila
atypical Protein Kinase C
Asymmetric cell division
Language English
License 2019. Published by The Company of Biologists Ltd.
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content type line 23
Present address: Cell Biology and Physiology Center, National Heart Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA.
These authors contributed equally to this work
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Snippet Studying the function of proteins using genetics in cycling cells is complicated by the fact that there is often a delay between gene inactivation and the time...
Studying the function of proteins using genetics in cycling cells is complicated by the fact that there is often a delay between gene inactivation and the...
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SubjectTerms Alleles
Animals
Cell Division
Cell Polarity
Drosophila melanogaster - embryology
Drosophila melanogaster - enzymology
Drosophila melanogaster - genetics
Drosophila Proteins - antagonists & inhibitors
Drosophila Proteins - genetics
Drosophila Proteins - metabolism
Embryo, Nonmammalian - cytology
Embryo, Nonmammalian - metabolism
Larva - cytology
Larva - metabolism
Loss of Function Mutation - genetics
Neurons - metabolism
Protein Kinase C - antagonists & inhibitors
Protein Kinase C - genetics
Protein Kinase C - metabolism
RNA Interference
Techniques and Resources
Title A chemical-genetics approach to study the role of atypical Protein Kinase C in Drosophila
URI https://www.ncbi.nlm.nih.gov/pubmed/30635282
https://search.proquest.com/docview/2179362385
https://pubmed.ncbi.nlm.nih.gov/PMC6361133
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