The integrin effector PINCH regulates JNK activity and epithelial migration in concert with Ras suppressor 1.
Cell adhesion and migration are dynamic processes requiring the coordinated action of multiple signaling pathways, but the mechanisms underlying signal integration have remained elusive. Drosophila embryonic dorsal closure (DC) requires both integrin function and c-Jun amino-terminal kinase (JNK) signaling for opposed epithelial sheets to migrate, meet, and suture. Here, we show that PINCH, a protein required for integrin-dependent cell adhesion and actin-membrane anchorage, is present at the leading edge of these migrating epithelia and is required for DC. By analysis of native protein complexes, we identify RSU-1, a regulator of Ras signaling in mammalian cells, as a novel PINCH binding partner that contributes to PINCH stability. Mutation of the gene encoding RSU-1 results in wing blistering in Drosophila, demonstrating its role in integrin-dependent cell adhesion. Genetic interaction analyses reveal that both PINCH and RSU-1 antagonize JNK signaling during DC. Our results suggest that PINCH and RSU-1 contribute to the integration of JNK and integrin functions during Drosophila development.
Kadrmas
Julie L
JL
Huntsman Cancer Institute, University of Utah, Salt Lake City, UT 84112, USA.
Smith
Mark A
MA
Clark
Kathleen A
KA
Pronovost
Stephen M
SM
Muster
Nemone
N
Yates
John R
JR
Beckerle
Mary C
MC
D000199:Actins / Q000502:physiology; D000818:Animals; D030801:Animals, Genetically Modified; D002448:Cell Adhesion / Q000502:physiology; D002465:Cell Movement / Q000502:physiology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D004330:Drosophila / Q000196:embryology / Q000201:enzymology / Q000235:genetics; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D004847:Epithelial Cells / Q000502:physiology; D004848:Epithelium / Q000196:embryology / Q000502:physiology*; D016023:Integrins / Q000378:metabolism / Q000502:physiology*; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D009154:Mutation; D015398:Signal Transduction / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism* / Q000502:physiology*; D014921:Wings, Animal / Q000502:physiology
D000199:Actins; D004268:DNA-Binding Proteins; D029721:Drosophila Proteins; D016023:Integrins; D014157:Transcription Factors; C495946:ics protein, Drosophila; C495947:stck protein, Drosophila; D048031:JNK Mitogen-Activated Protein Kinases