RRC ID 55616
Author Zhang P, Holowatyj AN, Roy T, Pronovost SM, Marchetti M, Liu H, Ulrich CM, Edgar BA.
Title An SH3PX1-Dependent Endocytosis-Autophagy Network Restrains Intestinal Stem Cell Proliferation by Counteracting EGFR-ERK Signaling.
Journal Dev Cell
Abstract The effect of intracellular vesicle trafficking on stem-cell behavior is largely unexplored. We screened the Drosophila sorting nexins (SNXs) and discovered that one, SH3PX1, profoundly affects gut homeostasis and lifespan. SH3PX1 restrains intestinal stem cell (ISC) division through an endocytosis-autophagy network that includes Dynamin, Rab5, Rab7, Atg1, 5, 6, 7, 8a, 9, 12, 16, and Syx17. Blockages in this network stabilize ligand-activated EGFRs, recycling them via Rab11-dependent endosomes to the plasma membrane. This hyperactivated ERK, calcium signaling, and ER stress, autonomously stimulating ISC proliferation. The excess divisions induced epithelial stress, Yki activity, and Upd3 and Rhomboid production in enterocytes, catalyzing feedforward ISC hyperplasia. Similarly, blocking autophagy increased ERK activity in human cells. Many endocytosis-autophagy genes are mutated in cancers, most notably those enriched in microsatellite instable-high and KRAS-wild-type colorectal cancers. Disruptions in endocytosis and autophagy may provide an alternative route to RAS-ERK activation, resulting in EGFR-dependent cancers.
Volume 49(4)
Pages 574-589.e5
Published 2019-5-20
DOI 10.1016/j.devcel.2019.03.029
PII S1534-5807(19)30240-0
PMID 31006650
PMC PMC6542281
MeSH Animals Autophagy / physiology Autophagy-Related Proteins / metabolism Cell Differentiation / physiology Cell Membrane / metabolism Cell Proliferation / physiology Drosophila Proteins / metabolism* Drosophila melanogaster / cytology* Drosophila melanogaster / metabolism Endocytosis Endosomes / metabolism ErbB Receptors / metabolism* Intestinal Mucosa / cytology* Intestinal Mucosa / metabolism Intracellular Signaling Peptides and Proteins / metabolism* MAP Kinase Signaling System* Protein Transport RNA Polymerase II / genetics RNA Polymerase II / metabolism Receptors, Invertebrate Peptide / metabolism* Signal Transduction / physiology Sorting Nexins / metabolism Stem Cells / cytology* Stem Cells / metabolism rab GTP-Binding Proteins / metabolism
IF 9.19
Times Cited 13
Drosophila 8056R-3 1395R-1