Caspase-mediated proteolysis of the sorting nexin 2 disrupts retromer assembly and potentiates Met/hepatocyte growth factor receptor signaling.
The unfolding of apoptosis involves the cleavage of hundreds of proteins by the caspase family of cysteinyl peptidases. Among those substrates are proteins involved in intracellular vesicle trafficking with a net outcome of shutting down the crucial processes governing protein transport to organelles and to the plasma membrane. However, because of the intertwining of receptor trafficking and signaling, cleavage of specific proteins may lead to unintended consequences. Here we show that in apoptosis, sorting nexin 1 and 2 (SNX1 and SNX2), two proteins involved in endosomal sorting, are cleaved by initiator caspases and also by executioner caspase-6 in the case of SNX2. Moreover, SNX1 is cleaved at multiple sites, including following glutamate residues. Cleavage of SNX2 results in a loss of association with the endosome-to-trans-Golgi network transport protein Vps35 and in a delocalization from endosomes of its associated partner Vps26. We also demonstrate that SNX2 depletion causes an increase in hepatocyte growth factor receptor tyrosine phosphorylation and Erk1/2 signaling in cells. Finally, we show that SNX2 mRNA and protein levels are decreased in colorectal carcinoma and that lowerSNX2gene expression correlates with an increase in cancer patient mortality. Our study reveals the importance to characterize the cleavage fragments produced by caspases of specific death substrates given their potential implication in the mechanism of regulation of physiological (signaling/trafficking) pathways or in the dysfunction leading to pathogenesis.
Department of Pharmacology-Physiology and Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001, 12th Avenue North, Sherbrooke, QC, Canada J1H 5N4.
Catherine M
CM
Duclos
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001, 12th Avenue North, Sherbrooke, QC, Canada J1H 5N4.
Audrey
A
Champagne
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001, 12th Avenue North, Sherbrooke, QC, Canada J1H 5N4.
Julie C
JC
Carrier
Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001, 12th Avenue North, Sherbrooke, QC, Canada J1H 5N4.
Caroline
0000-0001-7678-9886
C
Saucier
Department of Pharmacology-Physiology and Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001, 12th Avenue North, Sherbrooke, QC, Canada J1H 5N4.
Christine L
CL
Lavoie
Department of Pharmacology-Physiology and Institut de Pharmacologie de Sherbrooke, Faculty of Medicine and Health Sciences, Université de Sherbrooke , 3001, 12th Avenue North, Sherbrooke, QC, Canada J1H 5N4.
Jean-Bernard
JB
Denault