PAR-1 kinase regulates epithelial detachment and directional protrusion of migrating border cells.
BACKGROUND
Many cells that migrate during normal embryonic development or in metastatic cancer first detach from an epithelium. However, this step is often difficult to observe directly in vivo, and the mechanisms controlling the ability of cells to leave the epithelium are poorly understood. In addition, once cells detach, they must assume a migratory phenotype, involving changes in cytoskeletal and signaling dynamics. Drosophila border cells provide a model system in which a combination of forward genetics and live-cell imaging can allow researchers to investigate the cellular and molecular mechanisms of epithelial cell detachment and migration in vivo.


RESULTS
We identified the Drosophila homolog of the serine/threonine kinase PAR-1 (MARK/Kin1) in a screen for mutations that disrupt border cell migration. Previous studies identified two proteins, Apontic and Notch, that indirectly affect border cell detachment by regulating transcription of downstream targets. In contrast, PAR-1 directly modulates apical-basal polarity between border cells and epithelial cells to promote detachment. Furthermore, PAR-1, but not the apical polarity complex protein PAR-3, promotes the directionality of transient cell protrusions, which border cells require for sensing the chemoattractant gradient.


CONCLUSIONS
We conclude that PAR-1-dependent apical-basal polarity is required for proper detachment of migratory border cells from neighboring epithelial cells. Moreover, polarity controlled by PAR-1 influences the ability of migratory cells to sense direction, a critical feature of migration. Thus, this work reveals new insights into two distinct, but essential, steps of epithelial cell migration.
McDonald
Jocelyn A
JA
Department of Molecular Genetics, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA. mcdonaj@ccf.org
Khodyakova
Anna
A
Aranjuez
George
G
Dudley
Colleen
C
Montell
Denise J
DJ
D000091162:AMP-Activated Protein Kinase Kinases; D000818:Animals; D002448:Cell Adhesion; D002465:Cell Movement; D016764:Cell Polarity; D022081:Cell Surface Extensions / Q000502:physiology; D004330:Drosophila / Q000166:cytology*; D029721:Drosophila Proteins / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology*; D038362:Glycogen Synthase Kinase 3; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*
D029721:Drosophila Proteins; D011494:Protein Kinases; C495775:LKB1 protein, Drosophila; D017346:Protein Serine-Threonine Kinases; D038362:Glycogen Synthase Kinase 3; C472496:Par-1 protein, Drosophila; D000091162:AMP-Activated Protein Kinase Kinases