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Published online 13 December 2004. doi:10.1083/jcb.200408090
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 167, Number 6, 1019-1024
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The integrin effector PINCH regulates JNK activity and epithelial migration in concert with Ras suppressor 1



Julie L. Kadrmas1, Mark A. Smith1,2, Kathleen A. Clark1,2, Stephen M. Pronovost1, Nemone Muster4, John R. Yates, III4, and Mary C. Beckerle1,2,3

1 Huntsman Cancer Institute and 2 Department of Biology and 3 Department of Oncological Sciences, University of Utah, Salt Lake City, UT 84112
4 Department of Cell Biology, Scripps Research Institute, La Jolla, CA 92037

Correspondence to Mary C. Beckerle: mary.beckerle{at}hci.utah.edu


Abstract

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.

J.L. Kadrmas and M.A. Smith contributed equally to this paper.

Abbreviations used in this paper: bsk, basket; DC, dorsal closure; ics, icarus; ILK, integrin-linked kinase; JNK, c-Jun amino-terminal kinase; LE, leading edge; Msn, Misshapen; Puc, Puckered; stck, steamer duck; TAP, tandem affinity purification.


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