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Cell Rep. 2016 Jan 26;14(3):440-448. doi: 10.1016/j.celrep.2015.12.049. Epub 2016 Jan 7.

Knockout of the PKN Family of Rho Effector Kinases Reveals a Non-redundant Role for PKN2 in Developmental Mesoderm Expansion.

Author information

1
Kinase Biology Laboratory, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
2
Protein Phosphorylation Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
3
Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK.
4
Instituto Medicina Molecular (iMM), Faculdade de Medicina da Universidade de Lisboa, 1649-028 Lisbon, Portugal.
5
Newlife Birth Defects Research Centre, Institute of Child Health, University College, London WC1N 1EH, UK.
6
John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK.
7
Genetic Manipulation Services, Francis Crick Institute, Clare Hall, Herts EN6 3LD, UK.
8
Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13125 Berlin, Germany.
9
Protein Phosphorylation Laboratory, Francis Crick Institute, 44 Lincoln's Inn Fields, London WC2A 3LY, UK; Division of Cancer Studies, King's College London, New Hunt's House, Saint Thomas Street, London SE1 1UL, UK. Electronic address: peter.parker@crick.ac.uk.
10
Kinase Biology Laboratory, John Vane Science Centre, Barts Cancer Institute, Queen Mary University of London, Charterhouse Square, London EC1M 6BQ, UK. Electronic address: a.cameron@qmul.ac.uk.

Abstract

In animals, the protein kinase C (PKC) family has expanded into diversely regulated subgroups, including the Rho family-responsive PKN kinases. Here, we describe knockouts of all three mouse PKN isoforms and reveal that PKN2 loss results in lethality at embryonic day 10 (E10), with associated cardiovascular and morphogenetic defects. The cardiovascular phenotype was not recapitulated by conditional deletion of PKN2 in endothelial cells or the developing heart. In contrast, inducible systemic deletion of PKN2 after E7 provoked collapse of the embryonic mesoderm. Furthermore, mouse embryonic fibroblasts, which arise from the embryonic mesoderm, depend on PKN2 for proliferation and motility. These cellular defects are reflected in vivo as dependence on PKN2 for mesoderm proliferation and neural crest migration. We conclude that failure of the mesoderm to expand in the absence of PKN2 compromises cardiovascular integrity and development, resulting in lethality.

KEYWORDS:

4-OHT; 4-hydroxytamoxifen; ES cells; Embryonic stem cells; MEF; NCCs; PKC; PKN; Protein kinase N; mouse embryonic fibroblasts; neural crest cells; protein kinase C

PMID:
26774483
PMCID:
PMC4733087
DOI:
10.1016/j.celrep.2015.12.049
[Indexed for MEDLINE]
Free PMC Article

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