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Zhang, P., Holowatyj, A.N., Roy, T., Pronovost, S.M., Marchetti, M., Liu, H., Ulrich, C.M., Edgar, B.A. (2019). An SH3PX1-Dependent Endocytosis-Autophagy Network Restrains Intestinal Stem Cell Proliferation by Counteracting EGFR-ERK Signaling.  Dev. Cell 49(4): 574--589.e5.
FlyBase ID
FBrf0242427
Publication Type
Research paper
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.

PubMed ID
PubMed Central ID
PMC6542281 (PMC) (EuropePMC)
Related Publication(s)
Note

Tumor suppressive autophagy in intestinal stem cells controls gut homeostasis.
Zhang et al., 2019, Autophagy 15(9): 1668--1670 [FBrf0243002]

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Secondary IDs
    Language of Publication
    English
    Additional Languages of Abstract
    Parent Publication
    Publication Type
    Journal
    Abbreviation
    Dev. Cell
    Title
    Developmental Cell
    Publication Year
    2001-
    ISBN/ISSN
    1534-5807 1878-1551
    Data From Reference
    Aberrations (1)
    Alleles (67)
    Genes (51)
    Human Disease Models (1)
    Natural transposons (1)
    Insertions (4)
    Experimental Tools (6)
    Transgenic Constructs (49)