No 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.

Highlights d A Drosophila SH3PX1-dependent endocytosis-autophagy network restrains ISC division d Endocytosis and autophagy control ISC division by counteracting EGFR-ERK activity d Genes in endocytosis and autophagy are frequently mutated in human cancers

Receptor for Activated C Kinase 1 (RACK1) is a cytoplasmic molecular scaffolding protein. Many diverse protein-binding partners involved in key signaling pathways are reported to bind to RACK1, suggesting a role for RACK1 in signal integration. However, because loss-of-function phenotypes for RACK1 in an intact organism have not yet been reported, our current understanding of RACK1 is limited. Using Drosophila melanogaster, we show that RACK1 is expressed at all developmental stages and in many tissues, with specific enrichment in the ovary. By characterizing an allelic series of RACK1 mutants, we demonstrate that RACK1 is essential at multiple steps of Drosophila development, particularly in oogenesis, where somatic RACK1 is required for proper germ-line function.